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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”