Truseltiq
infigratinib
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
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
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
Species: general tox
Rat (26-week) and dog (39-week)
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
Species: DART
Rat and rabbit (embryo-fetal development); no pre/postnatal study
“The potential maternal and embryo‐fetal developmental effects of infigratinib after once‐daily dosing was evaluated in female Wistar Han rats and female New Zealand White rabbits.”
Species: carcinogenicity
Not conducted (not required for the advanced cancer indication)
“No carcinogenicity studies have been conducted with infigratinib and are not required for the proposed indication.”
Surrogate used in
No surrogate used; infigratinib tested directly in rat and dog
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Study title / number: BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period / 2821‐002”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“After 26 or 39 weeks of infigratinib administration in rats and dogs, respectively, the main target organ was bone.”
Route in tox
Oral (gavage)
“Oral dosing in animals was consistent with the intended clinical route of administration for infigratinib.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat bone marrow micronucleus assays
“Infigratinib was not mutagenic in the bacterial reverse mutation test. Infigratinib was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay or an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies are not recommended for the proposed indication.”
Reproductive & developmental
Rat EFD: embryofetal death at 10 mg/kg/day, reduced fetal weight at ≥3 mg/kg/day, fetal abnormalities at all doses
“Increases in embryo‐fetal death, with corresponding reductions in the numbers of viable fetuses, were observed at 10 mg/kg/day, and reductions in mean fetal body weights were observed at 3 and 10 mg/kg/day. Fetal abnormalities were observed at increased incidences at all doses.”
Safety pharmacology
No significant cardiovascular effects in telemetered dogs; no neurobehavioral or respiratory effects in rats
“Infigratinib had no toxicologically significant effects on cardiovascular function in telemetered dogs or on neurobehavioral and respiratory functions in rats.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Infigratinib was not mutagenic in the bacterial reverse mutation test.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte chromosome aberration: negative
“Infigratinib was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay or an in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Infigratinib was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay or an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
Not conducted (not recommended for the proposed indication)
“Carcinogenicity studies are not recommended for the proposed indication.”
Carcinogenicity timing
Not conducted: not warranted for the proposed indication
“Carcinogenicity studies are not warranted to support a marketing application for the proposed indication.”
hERG / QT
hERG inhibited only at concentrations much higher than human peak exposure at 125 mg QD
“Infigratinib and the metabolites BHS697 and CQM157 inhibited hERG current but at concentrations that were much higher than peak exposure of each in humans at the recommended clinical dose of infigratinib (125 mg QD).”
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 Truseltiq 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: Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat) (FDA multi-discipline review, p. 43)
NOAEL / key findings
Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat)
“Targets of toxicity included bone (decreases in bone strength, decreases in total bone mineral density, and multifocal growth plate fractures) and liver (centrilobular vacuolation and mild focal necrosis in the rat).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Extensive tissue distribution including brain; specific uptake into melanin-containing structures in pigmented rats
“[14C]‐infigratinib was extensively distributed into peripheral tissues in rats after oral and IV doses, including brain, and was specifically taken up into melanin‐containing structures in pigmented rats.”
Modality-specific risk
FGFR-mediated calcium/phosphorus imbalance with ectopic mineralization; corneal, bone, teeth and skin toxicity
“When infigratinib was administered to rats and/or dogs for ≤13 weeks the important toxicities included changes in calcium/phosphorus homeostasis, ectopic tissue mineralization in multiple tissues, changes in the cornea, bone, epithelial tissues, teeth, and/or hair/skin.”
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.
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 Truseltiq 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: Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat) (FDA multi-discipline review, p. 43)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral gavage) with 13-week recovery
“BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“After 26 or 39 weeks of infigratinib administration in rats and dogs, respectively, the main target organ was bone.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development); no pre/postnatal study
“The potential maternal and embryo‐fetal developmental effects of infigratinib after once‐daily dosing was evaluated in female Wistar Han rats and female New Zealand White rabbits.”
Reproductive & developmental
Rat EFD: embryofetal death at 10 mg/kg/day, reduced fetal weight at ≥3 mg/kg/day, fetal abnormalities at all doses
“Increases in embryo‐fetal death, with corresponding reductions in the numbers of viable fetuses, were observed at 10 mg/kg/day, and reductions in mean fetal body weights were observed at 3 and 10 mg/kg/day. Fetal abnormalities were observed at increased incidences at all doses.”
PPND / ePPND: when
No pre- and postnatal development study conducted
“Pre‐ and Postnatal Development: No pre‐ or post‐natal studies have been conducted with infigratinib.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not required for the advanced cancer indication)
“No carcinogenicity studies have been conducted with infigratinib and are not required for the proposed indication.”
Carcinogenicity model
Not conducted (not recommended for the proposed indication)
“Carcinogenicity studies are not recommended for the proposed indication.”
Carcinogenicity timing
Not conducted: not warranted for the proposed indication
“Carcinogenicity studies are not warranted to support a marketing application for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Margins <1 at all doses in rat and dog toxicity studies vs human exposure at 125 mg QD
“The safety margins at all dose levels was <1 based on a comparison of Cmax or AUC values in rat and dog toxicity studies to the human exposure (6284 ng*hr/mL; Cycle 1, Day 15) at the recommended dose of 125 mg QD”
NOAEL / key findings
Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat)
“Targets of toxicity included bone (decreases in bone strength, decreases in total bone mineral density, and multifocal growth plate fractures) and liver (centrilobular vacuolation and mild focal necrosis in the rat).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse and rat xenografts of human FGFR2/3-altered tumors, including cholangiocarcinoma PDX with FGFR2 fusions
“Infigratinib exhibited anti‐tumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including patient‐derived xenograft models of cholangiocarcinoma with FGFR2‐fusions.”
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 the cholangiocarcinoma indication
“The submitted nonclinical pharmacology and toxicology data are adequate to support the indication of infigratinib for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
Safety margins below 1 at all dose levels in rat and dog toxicity studies versus human exposure at 125 mg QD
Why: Greater sensitivity of nonclinical species to FGFR inhibition; mechanism-related findings monitorable and manageable in patients · Pharmacology or kinetics · Serious disease
“The safety margins at all dose levels was <1 based on a comparison of Cmax or AUC values in rat and dog toxicity studies to the human exposure (6284 ng*hr/mL; Cycle 1, Day 15) at the recommended dose of 125 mg QD, reflecting the greater sensitivity of the nonclinical species in the toxicology program to the pharmacologic effects (ie, inhibition of FGFR1‐3) of infigratinib.”
“The overall toxicity profile of infigratinib includes mechanism‐related findings that can be monitored and/or are considered clinically manageable in the intended patient population. The FDA’s Assessment: FDA generally agrees with the Applicant’s position.”
Safety marginVerdict not stated
Rat developmental toxicity NOAEL could not be determined (<1 mg/kg/day)
“The NOAEL for developmental toxicity could not be determined (<1 mg/kg/day).”
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