Balversa
erdafitinib
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
“Repeat Dose Toxicology Studies: The Applicant conducted oral repeat-dose general toxicology studies (up to 13 weeks) of erdafitinib in rats and dogs.”
Why that species
Erdafitinib is pharmacologically active in both rat and dog
“Rats and dogs were selected as relevant species for the pivotal 1- and 3-month repeat-dose toxicology studies since erdafitinib was shown to be pharmacologically active in both animal species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat Dose Toxicology Studies: The Applicant conducted oral repeat-dose general toxicology studies (up to 13 weeks) of erdafitinib in rats and dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“Repeat Dose Toxicology Studies: The Applicant conducted oral repeat-dose general toxicology studies (up to 13 weeks) of erdafitinib in rats and dogs.”
Pivotal GLP studies
1- and 3-month oral studies in rats and dogs
“Rats and dogs were selected as relevant species for the pivotal 1- and 3-month repeat-dose toxicology studies since erdafitinib was shown to be pharmacologically active in both animal species.”
Route in tox
Oral
“Repeat-dose oral toxicity was evaluated in albino Swiss mice dosed for up to 2 weeks, in Sprague-Dawley rats and Beagle dogs dosed for up to 3 months.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and in vivo rat bone marrow micronucleus assays
“Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”
Reproductive & developmental
Rat EFD: embryo-fetal death, vascular and limb malformations at >=4 mg/kg/day, below human exposure
“Doses ≥4 mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.”
Safety pharmacology
hERG IC50 408 nM; QT prolongation and arrhythmia potential in hERG and ventricular wedge assays
“In vitro, results from the hERG (IC50 408 nM [or 182 ng/mL]) and ventricular wedge assays demonstrated that erdafitinib has potential for producing QT prolongation and arrhythmia”
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 Balversa 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: Aorta/heart mineralisation, chondroid dysplasia of bone, epithelial atrophy of tongue, oral mucosa, salivary and lacrimal glands, eye, teeth (EMA assessment report, p. 33)
NOAEL / key findings
Aorta/heart mineralisation, chondroid dysplasia of bone, epithelial atrophy of tongue, oral mucosa, salivary and lacrimal glands, eye, teeth
“The predominant target organs were aorta (vascular/degeneration), heart (mineralisation/degeneration), bone femur and sternum (chondroid dysplasia), skin (increased hair follicles) and epithelial atrophy in the tongue, oral mucosa, parotid salivary glands, eye, teeth and lacrimal glands.”
Risksopen answer page →
Immune & cytokine safety
Skin sensitiser in the murine local lymph node assay
“Erdafitinib was considered to cause skin sensitization in the murine local lymph node assay”
Biodistribution & persistence
Prolonged retention in eye (t1/2 182.5 h) and lacrimal gland (t1/2 135.7 h)
“By 24/72 hours post dose, radioactivity was either close to or below the limit of quantification in the majority of the tissues, except the eye (T1/2 182.5 hours) and lacrimal gland (T1/2 135.7 hours).”
Modality-specific risk
Ocular toxicity (corneal atrophy) translating to clinical dry eye and keratitis
“Similar to animals, in patients treated with erdafitinib, dry eye and keratitis (inflammation of cornea) were reported, although the corneal opacities and atrophy found in animals were not noted in patients (possibly due to intervention/use of lubricating drops).”