Qinlock
ripretinib
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
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Why that species
Rat and dog form the same metabolites as humans
“The justification for the relevance of these test species includes: in vitro studies of metabolic stability and metabolite identification comparing mouse, rat, dog, monkey, and human, where rat and/or dog were demonstrated to form the same metabolites as humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Species: general tox
Rat and dog (up to 13 weeks)
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Species: DART
Rat (pivotal EFD) and rabbit (dose-range-finding EFD); no fertility or pre/postnatal studies (ICH S9)
“The conducted studies included dose-range finding embryo-foetal development studies in rats and rabbits and a pivotal embryo-foetal development study in rats.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with ripretinib.”
Surrogate used in
No surrogate used; ripretinib tested directly in rats and dogs
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Pivotal GLP studies
4- and 13-week oral studies in rats and dogs, with 4-week recovery
“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”
Route in tox
Oral
“The oral route of administration was utilized in all pivotal toxicology studies to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration, and in vivo rat micronucleus and comet assays
“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”
Reproductive & developmental
Rat EFD: cardiovascular and skeletal fetal malformations at 20 mg/kg (~0.4x clinical exposure)
“At the dose of 20 mg/kg daily (approximately 0.4 times the estimated clinical exposure at 150 mg), fetal malformations associated with the cardiovascular and skeletal systems were observed.”
Safety pharmacology
Dog telemetry: heart rate up to +129%, raised diastolic and mean arterial pressure, no QTc effect
“A single dose of ripretinib in beagle dogs resulted in increases in heart rate of up to 129% with secondary decreases in QT and PR intervals, as well as increases in diastolic and mean arterial pressure starting at 7 mg/kg; however, ripretinib did not appear to influence QTc intervals.”
Genotox: Ames
Negative (ripretinib and DP-5439)
“Both ripretinib and DP-5439 were found negative in the bacterial mutation assay.”
Genotox: in vitro mammalian
In vitro micronucleus (human lymphocytes): positive for ripretinib, negative for DP-5439
“Ripretinib, but not DP-5439, was found positive in the in vitro micronucleus assay using human peripheral blood lymphocytes.”
Genotox: in vivo
Rat micronucleus and comet assays: negative
“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”
Carcinogenicity timing
Not required for the advanced cancer indication
“The Regulatory Authorities agree that carcinogenicity was not warranted for the proposed indication.”
hERG / QT
hERG IC50 7.9 µM; negligible inhibition expected in vivo; no QTc effect in dog telemetry
“The average hERG IC50 value = 7.9 μM for ripretinib. Given the single‐ and double‐digit nanomolar inhibition of KIT and PDGFRα mutants in vitro, the high concentrations required for inhibition of the hERG channel in this assay would likely result in negligible inhibition in vivo.”
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 Qinlock 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: Skin was the major target in both species; teeth, lung and male reproductive tract also in rats (FDA multi-discipline review, p. 39)
NOAEL / key findings
Skin was the major target in both species; teeth, lung and male reproductive tract also in rats
“The major target organ of toxicity in both species was the skin; in the rat, the teeth, lung, and male reproductive tract were additional target organs.”
Risksopen answer page →
Immune & cytokine safety
Reduced thymus weight with decreased lymphocytes in dogs
“The weight of the thymus was reduced which correlated with the decreased number of lymphocytes observed microscopically.”
Biodistribution & persistence
Extensive, long-lived melanin binding in pigmented eye tissues (rat QWBA)
“Radiolabel associated with [14C]-ripretinib was extensively bound to melanin-containing tissues in pigmented LE rats such as eye ciliary body, eye uveal tract, and eyes, and the radiolabel binding showed a long half-life.”
Modality-specific risk
Phototoxic potential of ripretinib and its active metabolite DP-5439 (positive 3T3 NRU assay)
“Ripretinib and the active metabolite DP-5439 were investigated in the 3T3 NRU assay. Both substances demonstrated phototoxic potential in the assay.”
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 applicable
“Immunogenicity The Applicant’s Position: Not applicable The Regulatory Authorities’ Assessment: Not applicable.”
Label warnings
- Palmar-Plantar Erythrodysesthesia Syndrome
- New Primary Cutaneous Malignancies
- Hypertension
- Cardiac Dysfunction
- Risk of Impaired Wound Healing
- Photosensitivity
- Embryo-Fetal Toxicity
Secondary malignancySkin reactionsCardiovascularEmbryo-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 Qinlock 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: Skin was the major target in both species; teeth, lung and male reproductive tract also in rats (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog oral studies, each with 4-week recovery
“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”
Pivotal GLP studies
4- and 13-week oral studies in rats and dogs, with 4-week recovery
“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”
DART package
Species: DART
Rat (pivotal EFD) and rabbit (dose-range-finding EFD); no fertility or pre/postnatal studies (ICH S9)
“The conducted studies included dose-range finding embryo-foetal development studies in rats and rabbits and a pivotal embryo-foetal development study in rats.”
Reproductive & developmental
Rat EFD: cardiovascular and skeletal fetal malformations at 20 mg/kg (~0.4x clinical exposure)
“At the dose of 20 mg/kg daily (approximately 0.4 times the estimated clinical exposure at 150 mg), fetal malformations associated with the cardiovascular and skeletal systems were observed.”
PPND / ePPND: when
No PPND conducted; not warranted for advanced cancer per ICH S9
“The reproductive toxicity program is in accordance with ICH S9 guideline which states that studies on fertility and early embryonic development, and pre-and postnatal toxicology studies are generally not warranted to support marketing of pharmaceuticals for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with ripretinib.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”
Carcinogenicity timing
Not required for the advanced cancer indication
“The Regulatory Authorities agree that carcinogenicity was not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog NOAEL exposures below patient exposure (margins below 1)
“Exposure margins between the NOAEL and patient exposures were below 1.”
NOAEL / key findings
Skin was the major target in both species; teeth, lung and male reproductive tract also in rats
“The major target organ of toxicity in both species was the skin; in the rat, the teeth, lung, and male reproductive tract were additional target organs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse tumour xenografts: KIT exon 11 GIST T1, imatinib-resistant exon 17 GIST patient-derived xenograft
“In vivo inhibition of KIT was associated with inhibition of tumour growth in a variety of tumour xenograft models including exon 11 mutant KIT GIST T1 xenografts and an imatinib-resistant exon 17 mutant KIT GIST patient-derived xenograft.”
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
FDA generally agreed with the applicant's pharmacology study results
“The Regulatory Authorities generally agree with the study results described above.”
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
No in vivo phototoxicity follow-up after a positive in vitro 3T3 NRU assay, contrary to ICH S10 and CHMP advice
Why: Photosensitivity seen in patients; precautionary measures would remain regardless; similar restrictions for the class · Human data · Class precedent
“The justification is basically that there is no need for a follow up. This statement is in contrast to the ICH S10 Guidance on photosafety evaluation of pharmaceuticals as well as the advice given by CHMP.”
“However, it is considered unlikely that the currently proposed precautionary measures would be removed as a consequence of a negative in vivo phototoxicity study since photosensitivity reactions have been observed in 2 patients. Furthermore, similar restrictions are included for substances in the same class.”
Safety marginVerdict not stated
Exposure margins at rat and dog NOAELs below 1 relative to patient exposure
“The revised margins did not change the conclusion that exposure margins between NOAEL and patient exposures were below 1.”
Safety marginVerdict not stated
Rat embryo-fetal NOAEL exposure only 0.02 times clinical exposure
“The exposure margin based on AUC at NOAEL in the pivotal embryo-foetal development study in rat vs clinical exposure in humans was 0.02.”
Similar precedents
AyvakitSmall molecules · avapritinib · KIT/PDGFRARodent + dog or minipig · 39 wkLartruvoAntibodies · olaratumab · PDGFRαMonkey only · 39 wkBalversaSmall molecules · erdafitinib · FGFR1-4Rodent + dog or minipig · 13 wkEnsacoveSmall molecules · ensartinib · ALKRodent + dog or minipig · 13 wkExkivitySmall molecules · mobocertinib · EGFR exon 20 insertionRodent + dog or minipig · 13 wkFruzaqlaSmall molecules · fruquintinib · VEGFR1-3Rodent + dog or minipig · 13 wk