Jideytro
zidesamtinib
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
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Why that species
Metabolite profiles similar to human (including M9) and ability to achieve adequate systemic exposure
“The Wistar-Han rat and beagle dog were selected as appropriate species for toxicity based on having metabolite profiles similar to human (inclusive of the main des-ethyl metabolite in patients designated M9) and ability to achieve adequate systemic exposure.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Species: general tox
Rat (Wistar-Han) and Beagle dog
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted (ICH S9)
“No fertility, early embryonic development, prenatal, or postnatal development studies were conducted with zidesamtinib, and no studies are planned per International Conference on Harmonization (ICH) S9. In a GLP embryo-fetal development study in rats (Table 15), selective developmental toxicity was observed”
Species: carcinogenicity
Not conducted (ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Surrogate used in
No surrogate used; zidesamtinib tested directly in rats and dogs
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Pivotal GLP studies
28-day and 13-week oral twice-daily GLP studies in rats and dogs
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Route in tox
Oral (twice daily)
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs. Oral administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Positive in in vivo rat micronucleus assays; negative in Ames and in vitro TK6 clastogenicity assay
“Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Reproductive & developmental
Rat EFD: 100% post-implantation loss at ≥8 mg/kg/day (about 3.5x human AUC)
“There was 100% post-implantation loss at ≥8 mg/kg/day (approximately 3.5 times the human exposure based on AUC at the recommended dose).”
Safety pharmacology
hERG IC50 73.9 µM (~161-fold free Cmax); 11% QTc increase in telemetered dogs at 30 mg/kg
“zidesamtinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 73.9 µM, which is approximately 161-fold higher than the human free steady-state Cmax. Additional cardiovascular safety pharmacology assessment identified an 11% increase in QTc prolongation in telemetered conscious dogs following a single oral administration of zidesamtinib at 30 mg/kg/day.”
Genotox: Ames
Negative (with and without S9)
“In the standard genotoxicity battery, zidesamtinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay in the presence or absence of microsomal S9 mix.”
Genotox: in vitro mammalian
In vitro clastogenicity assay in human lymphoblastoid TK6 cells: negative
“Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”
Genotox: in vivo
Rat micronucleus (peripheral blood reticulocytes): positive; liver comet assay: negative
“However, zidesamtinib was genotoxic in vivo, inducing micronuclei formation in peripheral blood reticulocytes of rats following once daily oral administration for 2 or 4 days. A comet assay was negative for DNA damage in liver cells.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Carcinogenicity timing
Not conducted; not warranted for advanced cancer (ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
hERG / QT
hERG IC50 73.9 µM (~161-fold free Cmax); 11% QTc increase in telemetered dogs at 30 mg/kg
“zidesamtinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 73.9 µM, which is approximately 161-fold higher than the human free steady-state Cmax. Additional cardiovascular safety pharmacology assessment identified an 11% increase in QTc prolongation in telemetered conscious dogs following a single oral administration of zidesamtinib at 30 mg/kg/day.”
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 Jideytro 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: Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species) (FDA multi-discipline review, p. 37)
NOAEL / key findings
Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species)
“The major target organs of zidesamtinib in the 13-week studies included the pancreas and liver (rats), CNS (dogs), and gastrointestinal (GI) tract and lymphoid organs (both species).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent lymphoid depletion (GALT, lymph nodes, spleen, thymus) in dogs, incompletely reversible at 4 mg/kg/day
“Dogs had dose-dependent decreased cellularity of lymphoid tissues, including gut-associated lymphoid tissue (GALT), lymph nodes, spleen, and thymus, which did not completely resolve in the 4 mg/kg/day group.”
Biodistribution & persistence
Rapid wide tissue distribution in rats (within 15 minutes), including male reproductive and melanin-pigmented tissues (uvea, skin)
“Following a single oral dose to rats, 14C-zidesamtinib distributed to nearly all tissues within 15 minutes. Radioactivity was detected in male reproductive tissues (seminal vesicle, prostate gland, epididymis, and testes) and melanin-pigmented tissues (uveal tract and skin).”
Modality-specific risk
Off-target TRK inhibition: CNS toxicity and embryo-fetal toxicity
“the totality of the nonclinical and clinical data demonstrates a functional off-target TRK inhibition by zidesamtinib, which can have safety implications for both CNS toxicity and embryo-fetal development (discussed below).”
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 FDA’s Assessment: Not applicable.”
Label warnings
- Central Nervous System Adverse Reactions
- QTc Interval Prolongation
- Interstitial Lung Disease/Pneumonitis
- Skeletal Fractures
- Myalgia with Creatine Phosphokinase Elevation
- Pancreatic Toxicity
- Embryo-Fetal Toxicity
NeurotoxicityCardiovascularImmune-mediated reactionsPulmonary toxicityMusculoskeletalGastrointestinalEmbryo-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 Jideytro 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: Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species) (FDA multi-discipline review, p. 37)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral rat study with 4-week recovery; 13-week dog study of equal length also had a recovery period
“13-Week Oral Toxicity Study of NVL-520 with a 4-Week Recovery Period in Wistar Han Rats/ ID # NVL-520-NCTX-001”
Pivotal GLP studies
28-day and 13-week oral twice-daily GLP studies in rats and dogs
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
DART package
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted (ICH S9)
“No fertility, early embryonic development, prenatal, or postnatal development studies were conducted with zidesamtinib, and no studies are planned per International Conference on Harmonization (ICH) S9. In a GLP embryo-fetal development study in rats (Table 15), selective developmental toxicity was observed”
Reproductive & developmental
Rat EFD: 100% post-implantation loss at ≥8 mg/kg/day (about 3.5x human AUC)
“There was 100% post-implantation loss at ≥8 mg/kg/day (approximately 3.5 times the human exposure based on AUC at the recommended dose).”
PPND / ePPND: when
No PPND study: not warranted for advanced cancer (ICH S9)
“FDA agrees that fertility, early embryonic development, and pre- and postnatal development studies were not warranted to support the use of zidesamtinib in the proposed indication per ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Carcinogenicity timing
Not conducted; not warranted for advanced cancer (ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat lymphoid depletion at exposures comparable to human AUC (males) and ~1.7x (females); no NOAEL multiple stated
“Rats had dose-dependent increased incidence and severity of decreased lymphocytes in the marginal zone of the spleen and thymus in females at ≥3 mg/kg/day (approximately 1.7-times the human exposure based on AUC) and ≥6 mg/kg/day in males (comparable to human exposure).”
NOAEL / key findings
Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species)
“The major target organs of zidesamtinib in the 13-week studies included the pancreas and liver (rats), CNS (dogs), and gastrointestinal (GI) tract and lymphoid organs (both species).”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived xenograft (PDX) mouse models of ROS1-fusion NSCLC (SDC4-ROS1, CD74-ROS1 G2032R)
“In vivo, zidesamtinib demonstrated anti-tumor activity in patient-derived xenograft (PDX) murine models bearing subcutaneous NSCLC tumors expressing SDC4-ROS1 or CD74-ROS1G2032R following twice daily oral treatment at ≥0.2 mg/kg (SDC4-ROS1) or ≥1 mg/kg (CD74-ROS1G2032R).”
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 primary pharmacology assessment, objecting only to subjective, potentially promotional terminology
“FDA generally agrees with the Applicant’s assessment of primary pharmacology; however, terminology such as is subjective and should be avoided as it may be considered promotional.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a condition
No fertility or pre- and postnatal development studies, so neurodevelopmental effects of TRK inhibition were not assessed
Why: Not warranted for advanced cancer; TRK neurodevelopmental risk described in labeling · Within the guideline · Serious disease
“A pre- and postnatal development study may be capable of evaluating some of these endpoints; however, these studies are not warranted for drugs intended to treat patients with advanced cancer.”
“Based on these data, additional information regarding the effect of TRK inhibition on embryo-fetal development was added to the label.”
Impurity or metaboliteAcceptedBeyond the letter
Genotoxicity of major human metabolite M9 not directly tested
Why: Parent drug is itself genotoxic · Other reason
“The genetic toxicity of the M9 metabolite was not directly tested and is not warranted since the active pharmaceutical ingredient (i.e., zidesamtinib) is genotoxic.”
Similar precedents
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