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.”
Species: general tox
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.”
Species: DART
Rat (EFD) only; fertility and pre/postnatal studies not performed (ICH S9/S5)
“The reproductive and developmental toxicity of erdafitinib was investigated in a non-GLP pilot study and a GLP pivotal embryo-foetal toxicity study in Sprague-Dawley rats. In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“In accordance with ICH S9 guideline, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate used; erdafitinib itself tested in rats and dogs
“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”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
In vitro micronucleus in TK6 cells: negative
“In vitro, erdafitinib was negative for an increase in reverse mutations in Ames tests in bacteria and for chromosomal aberrations, polyploidy and endoreduplication in a micronucleus test in TK6 cells, respectively.”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 1000 mg/kg
“JNJ-42756493-AAA at doses up to and including a dose of 1000 mg/kg was negative in the bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”
Carcinogenicity timing
Not conducted or required for advanced cancer
“Carcinogenicity Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”
hERG / QT
Positive: hERG IC50 408 nM; hERG and ventricular wedge assays indicate QT prolongation and arrhythmia potential
“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)
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: 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).”
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
- Ocular Disorders
- 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 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)
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: Aorta/heart mineralisation, chondroid dysplasia of bone, epithelial atrophy of tongue, oral mucosa, salivary and lacrimal glands, eye, teeth (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and dog (oral); dog studies included a recovery period of unstated length
“In the pivotal 1-month (data not shown) and 3-month dog toxicology studies, no mortality was observed during the treatment window or in the recovery period.”
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.”
DART package
Species: DART
Rat (EFD) only; fertility and pre/postnatal studies not performed (ICH S9/S5)
“The reproductive and developmental toxicity of erdafitinib was investigated in a non-GLP pilot study and a GLP pivotal embryo-foetal toxicity study in Sprague-Dawley rats. In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”
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.”
PPND / ePPND: when
PPND not conducted, in line with ICH S9 and ICH S5(R3)
“In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“In accordance with ICH S9 guideline, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”
Carcinogenicity timing
Not conducted or required for advanced cancer
“Carcinogenicity Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: repeat-dose exposure multiples much lower than human AUC at 8 or 9 mg
“Thus, interpretation of the observed adverse effects is difficult since the exposure multiples following repeat dose administration of erdafitinib are much lower than the AUC in humans at the intended clinical dose of 8 or 9 mg.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumor cell-line xenografts with FGFR1, 2 and 3 alterations (bladder, lung, GI, liver) in immune-deficient rodents
“In vivo, erdafitinib demonstrated antitumor activity in immune-deficient rodents bearing tumors derived from multiple human cancer cell lines with FGFR1, 2 and 3 alterations (fusion or amplification) including the bladder, lung, GI and liver.”
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: activity in bladder cancer models at clinically relevant concentrations supports the indication
“Pharmacological activity of erdafitinib in bladder cancer models was observed at clinically relevant concentrations supporting the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginQuestioned
No exposure margin: animal-to-human exposure ratios below one at the highest doses in 3-month rat and dog studies
“The animal-to-human exposure ratios at the highest daily dose of 8 mg/kg and 0.75 mg/kg tested in the 3-month rat and dog study, respectively, are low (<1). Thus, interpretation of the observed adverse effects is difficult since the exposure multiples following repeat dose administration of erdafitinib are much lower than the AUC in humans at the intended clinical dose of 8 or 9 mg.”
Safety pharmacologyAccepted with a conditionBeyond the letter
Dog cardiovascular NOAEL only 2.4-fold clinical exposure; QT effect within clinical exposure range
Why: Risk addressed in the RMP and SmPC section 5.3
“The NOAEL was 2.5 mg/kg with Cmax of 12.4 ng/ml representing 2.4-fold of the expected clinical exposure which is not considered acceptable as a safety margins. As this effect appears in the clinical exposure range it is included in the RMP part II module SII and the SmPC section 5.3.”
DARTAccepted
No fertility or pre- and postnatal development studies; embryo-fetal studies in rats only
Why: ICH S9 and ICH S5(R3) for an advanced cancer indication · Within the guideline · Serious disease
“In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”
“Fertility and early embryonic development studies were not conducted or required to support an advanced cancer indication.”
Safety pharmacologyVerdict not stated
No dedicated CNS safety pharmacology study; CNS endpoints included in toxicology studies
Why: CNS endpoints included in the toxicology studies
“No dedicated safety pharmacology study was performed to evaluate CNS effects of erdafitinib. CNS endpoints were included in the toxicology studies and the effects are described in Toxicology section.”
Impurity or metaboliteAccepted
Potential genotoxic impurities controlled to non-mutagenic impurity limits (ICH Q3A) under ICH S9
Why: Erdafitinib not genotoxic; advanced cancer indication within ICH S9 · Within the guideline · Serious disease
“Erdafitinib (itself not genotoxic) is indicated for the treatment of patients with unresectable or metastatic urothelial carcinoma, to which ICH S9 applies. As such, potential genotoxic impurities may be controlled according to the limits for non-mutagenic impurities in ICH Q3A.”
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