Gavreto
pralsetinib
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 pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Why that species
Dog also tested but unsuitable beyond 7 days due to species-specific p38 MAPK-related toxicities; rat and monkey used
“The dog was also investigated as a non-rodent species, but due to species specific toxicities, related to p38 MAPK inhibition, and exacerbated toxicities following this inhibition, the dog was not suitable for further toxicity studies beyond single dose or 7 days repeat-dose studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the GLP-compliant 13-week repeated-dose toxicology study in rats (10 animals/sex/group), pralsetinib was administered at oral doses of 5, 10, and 20 mg/kg/day.”
Species: general tox
Sprague-Dawley rat and cynomolgus monkey (up to 13 weeks)
“The Applicant evaluated the safety of pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Species: DART
Rat only (fertility/early embryonic development and EFD)
“With respect to reproductive toxicity studies, a fertility and early embryonic development study and an extended dose range EFD study were performed in rats.”
Species: carcinogenicity
Not conducted (advanced cancer)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate used; pralsetinib tested directly
“In the GLP-compliant 13-week repeated-dose toxicology study in rats (10 animals/sex/group), pralsetinib was administered at oral doses of 5, 10, and 20 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The Applicant evaluated the safety of pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Pivotal GLP studies
28-day and 13-week GLP oral gavage studies in rats and cynomolgus monkeys
“The rat and cynomolgus monkey were used in GLP-compliant 28-days and 13-week repeat dose”
Route in tox
Oral gavage
“A GLP-compliant 13-Week Once Daily Oral Gavage Toxicity and Toxicokinetic Study of Pralsetinib in Sprague-Dawley Rats (Report 00124770)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and rat bone marrow micronucleus assays
“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Rat EFD: visceral and skeletal malformations from 5 mg/kg/day; 100% post-implantation loss at ≥20 mg/kg/day
“In the EFD study, multiple visceral and skeletal malformations were observed, as well as developmental variation, even from the lowest dose level of 5 mg/kg/day. 100% post implantation loss was seen at 20 mg/kg/day and above.”
Safety pharmacology
No relevant hERG inhibition or QTc prolongation in monkeys; increased blood pressure with decreased heart rate in rats at ≥25 mg/kg
“Pralsetinib did not inhibit in vitro hERG potassium currents at relevant concentrations or induce QTc prolongation in the 13-week repeat-dose study in cynomolgus monkeys. Single oral administration of ≥25 mg/kg pralsetinib resulted in increased blood pressure with concomitant decreases in heart rate in male Sprague-Dawley rats.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
In vitro micronucleus in TK6 cells: negative
“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
Not conducted (advanced cancer)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not needed for the advanced cancer indication (ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of pralsetinib in the currently proposed indication per ICH S9.”
hERG / QT
hERG IC50 5.18 µM (non-GLP); minimal QT prolongation risk
“The IC50 value of 5.18 µM (n=2) determined in the non-GLP in vitro hERG channel study (Study #CPB-25-15-010A-0169) suggests minimal risk of QT prolongation through this pathway in humans given pralsetinib.”
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 Gavreto 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: Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation) (FDA multi-discipline review, p. 42)
NOAEL / key findings
Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation)
“Target organs in both species included the bone marrow, with findings of decreased cellularity histopathologically consistent with decreases in red blood cells (RBCs) and mild decreases in white blood cells (WBCs), kidney (decreased weight and tubular basophilia/mineralization), and lung (macrophage aggregation).”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; decreased cellularity of haematopoietic and lymphoid organs in rats and monkeys
“Although no dedicated immunotoxicity studies were conducted with pralsetinib, some of the toxicological findings reported in repeat-dose toxicity studies were related to its actions on immune system (i.e., decreased cellularity of multiple haematopoietic and lymphoid organs in rats, and bone marrow cellularity and decreased cellularity of lymphoid organs in monkeys).”
Biodistribution & persistence
Wide distribution (intestine, liver, adrenal, uveal tract, pigmented skin); melanin affinity; crosses blood-brain barrier in rats
“Following single oral administration, 14C-pralsetinib-derived radioactivity distributed widely to rat tissues especially the small intestine wall, liver, adrenal gland, uveal tract, and pigmented skin. Pralsetinib crossed the blood-brain barrier in rats”
Modality-specific risk
Embryofetal toxicity: renal malformations consistent with the role of RET in renal organogenesis
“The observed renal malformations/variations were consistent with the role of RET in renal organogenesis. The pharmacology/toxicology team recommends a warning for embryo-fetal toxicity in the label for GAVRETO.”
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
Label warnings
Boxed warning: Serious infections, including opportunistic infections
- Serious Infections, Including Opportunistic Infections
- Interstitial Lung Disease/Pneumonitis
- Hypertension
- Hepatotoxicity
- Hemorrhagic Events
- Tumor Lysis Syndrome
- Risk of Impaired Wound Healing
- Embryo-Fetal Toxicity
InfectionsImmune-mediated reactionsPulmonary toxicityCardiovascularHepatotoxicityBleedingSecondary malignancyEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
First-in-human ARROW trial in patients: 80 centres in 14 countries including USA, UK, China, Germany
“80 centres/ 14 countries: Belgium, China France, Germany, Hong Kong, Italy, Korea, Netherlands, Singapore, Spain, Switzerland, Taiwan, UK, USA”
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 Gavreto 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: Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation) (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and cynomolgus monkey GLP studies; recovery not assessed
“Recovery was not assessed in the 13-week studies, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.”
Pivotal GLP studies
28-day and 13-week GLP oral gavage studies in rats and cynomolgus monkeys
“The rat and cynomolgus monkey were used in GLP-compliant 28-days and 13-week repeat dose”
DART package
Species: DART
Rat only (fertility/early embryonic development and EFD)
“With respect to reproductive toxicity studies, a fertility and early embryonic development study and an extended dose range EFD study were performed in rats.”
Reproductive & developmental
Rat EFD: visceral and skeletal malformations from 5 mg/kg/day; 100% post-implantation loss at ≥20 mg/kg/day
“In the EFD study, multiple visceral and skeletal malformations were observed, as well as developmental variation, even from the lowest dose level of 5 mg/kg/day. 100% post implantation loss was seen at 20 mg/kg/day and above.”
PPND / ePPND: when
No PPND study, per ICH S9 (advanced cancer)
“Studies on reproductive function, early embryonic development, pre- and postnatal development, and effects in juvenile animals were not conducted in accordance with ICH S9 guideline.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not needed for the advanced cancer indication (ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of pralsetinib in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week rat and monkey NOAEL (10 mg/kg/day) ~1x human AUC
“The No-Observed-Adverse-Effect-Level (NOAEL) of pralsetinib in the 13- week studies was 10 mg/kg/day in both species, corresponding to exposure (AUC) margins of 1 times relative to the human exposures.”
NOAEL / key findings
Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation)
“Target organs in both species included the bone marrow, with findings of decreased cellularity histopathologically consistent with decreases in red blood cells (RBCs) and mild decreases in white blood cells (WBCs), kidney (decreased weight and tubular basophilia/mineralization), and lung (macrophage aggregation).”
Efficacy evidenceopen answer page →
Efficacy evidence
RET-mutant and patient-derived RET-fusion (NSCLC, CRC) xenografts in mice
“Pralsetinib exhibited in vivo anti-tumor activity in mice bearing subcutaneously (SC)-implanted tumor xenografts bearing RET activating mutations, including the cabozantinib resistant mutation V804L, or patient-derived NSCLC and colorectal cancer (CRC) xenografts expressing KIF5B-RET and CCDC6-RET, respectively.”
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 vitro and in vivo proof of concept well established
“In vitro and in vivo proof of concept is considered well established.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Embryo-fetal toxicity in rat only; no second-species EFD, pre/postnatal, juvenile or immunotoxicity studies
Why: Consistent with ICH S9 for advanced-cancer products · Within the guideline
“Consistent with ICH guideline S9, the following non-clinical studies were not conducted: carcinogenicity studies, a confirmatory embryofoetal toxicity study in a second species, studies on pre/postnatal development, studies in juvenile animals, and immunotoxicity studies.”
GLPAcceptedBeyond the letter
No definitive GLP-compliant in vitro hERG study; only a non-GLP hERG study
Why: Available GLP safety studies plus the supportive non-GLP study provide sufficient safety data · Weight of evidence
“Though the Applicant did not submit a definitive GLP-compliant in vitro study, the available GLP-compliant safety studies have provided sufficient safety data along with this supportive study.”
RecoveryVerdict not stated
No recovery phase in the 13-week rat and monkey studies; bone and tooth findings incompletely recovered in 28-day rat study
“Recovery was not assessed in the 13-week studies, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.”
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