Pemazyre
pemigatinib
Species
MonkeyRat
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 cynomolgus monkey
“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”
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
“In the 13-week toxicology study in cynomolgus monkeys, there was no mortality at doses up to the high dose level, 1 mg/kg.”
Species: general tox
Sprague-Dawley rat and cynomolgus monkey
“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”
Species: DART
Rat (non-GLP dose range-finding EFD only); no fertility studies (advanced cancer)
“The Applicant conducted a non-GLP dose range-finding embryo-fetal development study in Sprague-Dawley rats. Because this study demonstrated clear findings at exposure levels below the clinical exposure at the 13.5 mg human dose, this study was sufficient to characterize the potential developmental risk.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Surrogate used in
No surrogate used; pemigatinib inhibits human and rat FGFR1/FGFR2 with similar affinity
“Pemigatinib inhibited recombinant human and rat FGFR1 and FGFR2 with similar affinity.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and monkey)
“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”
Pivotal GLP studies
GLP repeat-dose studies of up to 3 months in Sprague-Dawley rats and cynomolgus monkeys
“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”
Route in tox
Oral gavage
“Route of administration: Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat bone marrow micronucleus assays
“Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosomal aberration assay in human peripheral blood lymphocytes or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Reproductive & developmental
Rat EFD: 100% post-implantation loss at >=0.3 mg/kg (~0.6x human AUC)
“Once daily oral administration of pemigatinib to pregnant rats during the period of organogenesis (gestation Days 6 to 17) resulted in reduced maternal body weight and food consumption at dose levels ≥0.3 mg/kg (approximately 0.6 times the exposure based on AUC at the human dose of 13.5 mg) accompanied by 100% post-implantation loss (early resorptions).”
Safety pharmacology
hERG IC50 >8 µM; no QTc prolongation in single-dose monkey study or 13-week monkey study
“Pemigatinib inhibited the hERG potassium current with an IC50 >8 µM, which is not clinically achievable at the recommended dose of 13.5 mg. Consistent with this in vitro finding, pemigatinib did not induce QTc prolongation in a single-dose safety pharmacology study in cynomolgus monkeys or in the 13-week repeat-dose study in monkeys.”
Genotox: Ames
Negative
“Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
In vitro chromosome aberration assay: negative
“Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rats.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Carcinogenicity timing
Not required (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
hERG / QT
hERG IC50 >8 µM, not clinically achievable; no QTc prolongation in monkeys
“Pemigatinib inhibited the hERG potassium current with an IC50 >8 µM, which is not clinically achievable at the recommended dose of 13.5 mg.”
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 Pemazyre 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: Hyperphosphatemia with multi-organ soft tissue and vascular mineralization in rats at >=0.27 mg/kg (~0.4x human AUC) (FDA multi-discipline review, p. 35)
NOAEL / key findings
Hyperphosphatemia with multi-organ soft tissue and vascular mineralization in rats at >=0.27 mg/kg (~0.4x human AUC)
“Treatment with ≥0.27 mg/kg pemigatinib (approximately 0.4 times the exposure based on AUC at the human dose of 13.5 mg) induced hyperphosphatemia in rats, which correlated with firm/white areas in the aorta and vena cava and multi-organ histologic soft tissue and vascular mineralization.”
Risksopen answer page →
Immune & cytokine safety
Multi-organ mononuclear cell infiltration in rats and monkeys
“Pemigatinib induced multi-organ histologic mononuclear cell infiltration in both species.”
Biodistribution & persistence
Wide rat tissue distribution, especially excretory, endocrine, alimentary and pigmented tissues; minimal CNS
“Following single oral administration, 14C-pemigatinib-derived radioactivity distributed widely to rat tissues especially excretory, endocrine, alimentary canal, and pigmented tissues, but only minimally in CNS tissues.”
Modality-specific risk
On-target FGFR effects: hyperphosphatemia, mineralization, physeal dysplasia, bone and teeth toxicity
“Many of the pemigatinib-induced findings (e.g. hyperphosphatemia, mineralization, physeal dysplasia, and bone/teeth findings) were attributable to the primary pharmacology of FGFR inhibition.”
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 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
Country not stated; first-in-human study INCB 54828-101 was in patients with advanced malignancies
“Study INCB 54828-101 was an open-label, dose-escalation and expansion study of pemigatinib administered alone or in combination with another cancer therapy in participants with advanced malignancies.”
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 Pemazyre 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: Hyperphosphatemia with multi-organ soft tissue and vascular mineralization in rats at >=0.27 mg/kg (~0.4x human AUC) (FDA multi-discipline review, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (oral, GLP) with 6-week recovery
“In the 13-Week GLP study by oral gavage in Cynomolgus Monkeys with a 6-week recovery period, target organs were bone (physis) and cartilage plates of the sternum with a phosphorus increase.”
Pivotal GLP studies
GLP repeat-dose studies of up to 3 months in Sprague-Dawley rats and cynomolgus monkeys
“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”
DART package
Species: DART
Rat (non-GLP dose range-finding EFD only); no fertility studies (advanced cancer)
“The Applicant conducted a non-GLP dose range-finding embryo-fetal development study in Sprague-Dawley rats. Because this study demonstrated clear findings at exposure levels below the clinical exposure at the 13.5 mg human dose, this study was sufficient to characterize the potential developmental risk.”
Reproductive & developmental
Rat EFD: 100% post-implantation loss at >=0.3 mg/kg (~0.6x human AUC)
“Once daily oral administration of pemigatinib to pregnant rats during the period of organogenesis (gestation Days 6 to 17) resulted in reduced maternal body weight and food consumption at dose levels ≥0.3 mg/kg (approximately 0.6 times the exposure based on AUC at the human dose of 13.5 mg) accompanied by 100% post-implantation loss (early resorptions).”
PPND / ePPND: when
No PPND study conducted; not needed for the advanced cancer indication per ICH S9
“No studies on pre-postnatal development have been conducted with pemigatinib. The lack of pre-postnatal developmental studies is acceptable in view of the intended indication for Pemazyre and is in line with the ICH S9 guideline.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Carcinogenicity timing
Not required (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
No safety margin for soft tissue mineralisation and ocular findings in rats and monkeys
“There are no safety margins for the soft tissue mineralisation in rats and monkeys and ophthalmic findings for up to 90 days.”
NOAEL / key findings
Hyperphosphatemia with multi-organ soft tissue and vascular mineralization in rats at >=0.27 mg/kg (~0.4x human AUC)
“Treatment with ≥0.27 mg/kg pemigatinib (approximately 0.4 times the exposure based on AUC at the human dose of 13.5 mg) induced hyperphosphatemia in rats, which correlated with firm/white areas in the aorta and vena cava and multi-organ histologic soft tissue and vascular mineralization.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumour xenografts in mice with FGFR1-3 activation, incl. patient-derived FGFR2-TRA2B cholangiocarcinoma xenografts
“Pemigatinib exhibited in vivo anti-tumor activity in mice bearing subcutaneous (SC) human xenografts with FGFR1, FGFR2, or FGFR3 activation, including patient-derived cholangiocarcinoma xenografts expressing a FGFR2 TRA2B fusion and FGFR2-amplified human gastric cancer xenografts.”
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: in vivo antitumour activity shown across FGFR1-3-altered human tumour models, including patient-derived xenografts
“In vivo, pemigatinib demonstrated antitumour activity in rodents bearing tumours derived from multiple human cancer cell lines with FGFR1, 2, and 3 alterations (translocation or amplification) including gastric, cholangiocarcinoma, bladder, and in a mouse study using patient-derived xenografts originated from blood expressing FGFR1 fusion protein.”
Flexibilityopen answer page →
Flexibility accepted
GLPAcceptedBeyond the letter
Embryo-fetal development assessed only in a non-GLP dose range-finding rat study
Why: Clear developmental findings at exposures below clinical exposure at 13.5 mg · Weight of evidence
“The Applicant conducted a non-GLP dose range-finding embryo-fetal development study in Sprague-Dawley rats. Because this study demonstrated clear findings at exposure levels below the clinical exposure at the 13.5 mg human dose, this study was sufficient to characterize the potential developmental risk.”
DARTAccepted
No fertility and early embryonic development studies
Why: Advanced-cancer indication and teratogenicity already shown; in line with ICH S9 · Within the guideline · Serious disease
“Due to the indication of pemigatinib and the teratogenic effects observed in the range-finding embryo-foetal toxicity study, the lack of fertility and early embryonic developmental studies is acceptable and is in line with the recommendations given in the ICH S9 guideline.”
DARTAccepted
No pre- and postnatal development study
Why: Intended indication; in line with ICH S9 · Within the guideline · Serious disease
“No studies on pre-postnatal development have been conducted with pemigatinib. The lack of pre-postnatal developmental studies is acceptable in view of the intended indication for Pemazyre and is in line with the ICH S9 guideline.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity studies
Why: Adult-only indication; full paediatric waiver granted · Other reason
“Since the currently intended indication of Pemazyre is for treatment of adults, the lack of juvenile toxicity studies in animals is acceptable; pemigatinib was granted a full paediatric waiver for development for the treatment of either cholangiocarcinoma or urothelial carcinoma (EMA decision P/0386/2018).”
Safety marginVerdict not stated
No safety margin for soft tissue mineralisation (rats, monkeys) and ophthalmic findings
“There are no safety margins for the soft tissue mineralisation in rats and monkeys and ophthalmic findings for up to 90 days.”
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