Lytgobi
futibatinib
Species
RatDog
Longest study
13 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
“The Applicant conducted general toxicology studies in rats and dogs.”
Why that species
Similar metabolism in rat, dog and human
“A similar metabolism was seen in rat, dog and human, such as O-demethylation, mono- or di-oxidation, hydration, and Phase II (cysteine or N-acetylcysteine conjugation) conversion.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”
Species: general tox
Rat and dog
“The Applicant conducted general toxicology studies in rats and dogs.”
Species: DART
Rat (EFD only); no fertility or pre/postnatal studies, in line with ICH S9
“In line with ICH S9, no fertility, PPND or juvenile animals studies were performed.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with futibatinib have not been conducted.”
Surrogate used in
No surrogate used
“The Applicant conducted general toxicology studies in rats and dogs. Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”
Pivotal GLP studies
4-week and 13-week GLP oral studies in rats and dogs (daily or every other day)
“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”
Route in tox
Oral
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames; clastogenic in vitro chromosome aberration assay; negative rat micronucleus and comet assays
“Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Futibatinib was clastogenic in an in vitro chromosomal aberration assay after a 6 hour treatment. Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (comet) assay.”
Carcinogenicity
Not conducted; not recommended for the proposed indication
“Carcinogenicity studies have not been conducted with futibatinib and are not recommended for the proposed indication.”
Reproductive & developmental
Rat EFD: reduced fetal weight, skeletal and visceral malformations at 0.5 mg/kg/day (~0.2x clinical dose)
“Fetal survival was unaffected at 0.5 mg/kg per day; however, once daily oral administration of futibatinib at the 0.5 mg/kg dose level (approximately 0.2 times the recommended clinical dose of 20 mg based on BSA) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.”
Safety pharmacology
No significant effects on CV function in telemetered dogs or on CNS and respiratory function in rats
“Futibatinib had no toxicologically significant effects on cardiovascular function in telemetered dogs or on neurobehavioral and respiratory functions in rats.”
Genotox: Ames
Negative
“Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
In vitro chromosomal aberration assay: positive (clastogenic)
“Futibatinib was clastogenic in an in vitro chromosomal aberration assay.”
Genotox: in vivo
Rat bone marrow micronucleus and rat comet assays: negative
“Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (Comet) assay.”
Carcinogenicity model
Not conducted; not recommended for the proposed indication
“Carcinogenicity studies have not been conducted with futibatinib and are not recommended for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies are not recommended for the proposed indication.”
hERG / QT
hERG IC50 3105 ng/mL, much higher than dog Cmax at severely toxic dose (531 ng/mL) and human peak exposure; no QTc concern
“Futibatinib inhibited hERG current (Study No. 8215) but at concentrations that were much higher (IC50 value: 3105 ng/mL) than the Cmax observed at a severely toxic dose (531 ng/mL) in dogs and the peak exposure in humans at the recommended clinical dose of futibatinib (20 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 Lytgobi 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: Increased plasma phosphorus, ectopic mineralization in multiple tissues and bone lesions at clinically relevant exposures (FDA multi-discipline review, p. 42)
NOAEL / key findings
Increased plasma phosphorus, ectopic mineralization in multiple tissues and bone lesions at clinically relevant exposures
“Drug‐related findings in both species were consistent with FGFR inhibition including increases in plasma phosphorus, ectopic mineralization in multiple tissues, and lesions in bone at exposure levels that are in range with human exposures at the recommended clinical dose of 20 mg.”
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
Rat QWBA: radioactivity still high in uveal tract and retinal epithelial cells at 336 h; low in blood, kidney, heart, pigmented skin
“At 336 hrs post dose, radioactivity was still high in the uveal tract and retinal epithelial cells and low but measurable in blood, kidney, heart and skin (pigmented).”
Modality-specific risk
FGFR-related ectopic mineralization that did not recover after dosing stopped
“Evidence of recovery in rats and dogs was observed four weeks after cessation of dosing except for the ectopic mineralization.”
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 Data: Not Applicable”
Label warnings
- Ocular Toxicity
- Hyperphosphatemia and Soft Tissue Mineralization
- Embryo-Fetal Toxicity
Ocular toxicityMetabolic & endocrineEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
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 Lytgobi 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: Increased plasma phosphorus, ectopic mineralization in multiple tissues and bone lesions at clinically relevant exposures (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog (oral, daily or every other day), both with recovery phase
“In the pivotal 4-week and 13-week toxicology studies in rats and dogs, no mortality was observed during the treatment window or in the recovery period.”
Pivotal GLP studies
4-week and 13-week GLP oral studies in rats and dogs (daily or every other day)
“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”
DART package
Species: DART
Rat (EFD only); no fertility or pre/postnatal studies, in line with ICH S9
“In line with ICH S9, no fertility, PPND or juvenile animals studies were performed.”
Reproductive & developmental
Rat EFD: reduced fetal weight, skeletal and visceral malformations at 0.5 mg/kg/day (~0.2x clinical dose)
“Fetal survival was unaffected at 0.5 mg/kg per day; however, once daily oral administration of futibatinib at the 0.5 mg/kg dose level (approximately 0.2 times the recommended clinical dose of 20 mg based on BSA) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.”
PPND / ePPND: when
Not conducted: PPND not required for advanced cancer (ICH S9)
“In line with ICH S9, no fertility, PPND or juvenile animals studies were performed.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with futibatinib have not been conducted.”
Carcinogenicity model
Not conducted; not recommended for the proposed indication
“Carcinogenicity studies have not been conducted with futibatinib and are not recommended for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies are not recommended for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL; rat STD10 (10 mg/kg QOD) exposure approximately equals clinical exposure, no margin
“A severely toxic dose (STD10) was determined for QOD dosing of 10 mg/kg based on the cardiac mineralisation. There is no exposure multiple as this exposure corresponds to approximately the clinical exposure.”
NOAEL / key findings
Increased plasma phosphorus, ectopic mineralization in multiple tissues and bone lesions at clinically relevant exposures
“Drug‐related findings in both species were consistent with FGFR inhibition including increases in plasma phosphorus, ectopic mineralization in multiple tissues, and lesions in bone at exposure levels that are in range with human exposures at the recommended clinical dose of 20 mg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumor xenografts with FGFR2 alterations: AN3 CA endometrial carcinoma in nude mice and SNU-16 gastric carcinoma in nude rats
“Futibatinib had antitumor activity and inhibited FGFR2 phosphorylation and downstream AKT and ERK signaling in a human endometrial carcinoma mice model with an FGFR2 mutation. Antitumor activity was also observed in a nude rat model with human gastric carcinoma SNU‐16 xenograft tumors (FGFR2 gene amplification).”
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
EMA: xenograft studies give proof of concept that futibatinib inhibits growth of human FGFR2 cancer cell lines in vivo
“Proof of concept was shown using mice and rat studies where human FGFR2 cancer cell lines were implanted as xenografts. The growth of these xenografts was inhibited upon futibatinib administration, indicating that futibatinib is able to inhibit growth of human FGFR2 cancer cell line growth in vivo.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin: rat severely toxic dose (cardiac mineralisation) exposure approximately equals clinical exposure
“A severely toxic dose (STD10) was determined for QOD dosing of 10 mg/kg based on the cardiac mineralisation. There is no exposure multiple as this exposure corresponds to approximately the clinical exposure.”
DARTAccepted
No fertility, pre- and postnatal development or juvenile animal studies
Why: ICH S9 for advanced cancer · Within the guideline
“In line with ICH S9, no fertility, PPND or juvenile animals studies were performed.”
GLPAcceptedBeyond the letter
Bioanalytical methods supporting the GLP repeat-dose rat and dog studies not GLP compliant
Why: Methods adequately validated under domestic reliability standards and met pre-defined acceptance criteria · Other reason
“Analytical methods (C-AT120019 and C-AT120020) used in repeat dose toxicity studies in rats and dogs, however, are not GLP compliant. It was, however, sufficiently demonstrated that the analytical methods supporting GLP repeat dose toxicity studies were adequately validated, as these were in compliance with domestic reliability standards.”
“Moreover, performance parameters met the pre-defined acceptance criteria, set out by EMA Guideline on Analytical Methods ICHS3A.”
Impurity or metaboliteAccepted
Major human cysteinylglycine conjugate metabolite not observed in rat or dog
Why: Metabolites below 25% of parent exposure, inactive in vitro; indication within ICH S9 · Pharmacology or kinetics · Within the guideline
“Metabolism seems similar in human as in rat and dog with the exception of the major metabolite in human plasma cysteinylglycine conjugate (TAS-06-22952). This metabolite and also the glutathione conjugate were not observed in vitro and in vivo in rat and dog (see Non-clinical aspects).”
“The two primary circulating metabolites in human plasma, a cysteinylglycine conjugate (13%) and a cysteine conjugate (9%), were <25% of the exposure to the parent and showed no in vitro activity (Study CBS-200034). It is therefore agreed that further characterisation of the pharmacokinetics of metabolites is not needed, also considering the indication in the scope of ICH S9.”
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