Pemazyre
pemigatinib
Sources:FDA multi-discipline review ↗
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.”
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.”
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)
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: 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.”