Ibtrozi
taletrectinib
Species
MonkeyRat
Longest study
12 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 taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
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
“Report 2021010: 85-Day Repeated-Dose Toxicity Study of Taletrectinib by Oral Gavage in Cynomolgus Monkeys with a 57-Day Treatment-Free Period”
Species: general tox
Rat and cynomolgus monkey
“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Species: DART
Rat and rabbit (embryo-fetal development)
“GLP-compliant embryo-fetal development studies were conducted in pregnant rats and rabbits to assess the effect of taletrectinib on fetal development.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies have not been conducted with taletrectinib and are not warranted for the proposed indication.”
Surrogate used in
No surrogate used; taletrectinib tested directly in rats and monkeys
“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
12 (85-day rat and monkey)
“GLP-compliant 28-day and pivotal 85-day toxicity and TK studies in rats and monkeys confirmed that taletrectinib produced target organ toxicity that would be anticipated for a typical TKI.”
Pivotal GLP studies
28-day and 12-week oral studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Route in tox
Oral (gavage), once daily
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and additional mutagenicity tests and in the rat bone marrow/liver micronucleus assay
“Taletrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and additional mutagenicity tests. Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in bone marrow and liver.”
Carcinogenicity
Not conducted; not warranted for the proposed indication
“Carcinogenicity studies have not been conducted with taletrectinib and are not warranted for the proposed indication.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal mortality and structural abnormalities at or below human exposure
“In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose”
Safety pharmacology
hERG IC50 0.98 µM, hNav1.5 IC50 0.83 µM; no ECG or QTc effects in telemetered monkeys up to 100 mg/kg/day
“In vitro, taletrectinib inhibited hERG currents and hNav1.5 with IC50 values of 0.98 µM and 0.83 µM, respectively, indicating a potential effect on QT prolongation. However, in the telemetered monkey cardiovascular study, there were no effects on any electrocardiogram (ECG) parameters, including QTc at the highest non-severely toxic dose (HNSTD) of 100 mg/kg/day.”
Genotox: Ames
Negative (Ames assays)
“Taletrectinib was negative for mutagenicity in in vitro bacterial reverse mutation (Ames) assays and additional mutagenicity tests, including 2 mammalian cell gene mutation assays and one in vivo gene mutation assay in rats.”
Genotox: in vitro mammalian
In vitro chromosome aberration study: positive (structural and numerical aberrations)
“In an in vitro chromosome aberration study, taletrectinib was predicted to have the potential to induce structural and numerical aberrations.”
Genotox: in vivo
Rat micronucleus (liver and bone marrow): negative up to 300 mg/kg
“Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in liver or bone marrow when administered orally up to 300 mg/kg.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies are not planned as taletrectinib is intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required for the advanced ROS1-positive NSCLC indication
“FDA agrees that carcinogenicity studies are not warranted for the current indication of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).”
hERG / QT
hERG IC50 0.98 µM (potential QT effect); no ECG/QTc effects in telemetered monkeys at 100 mg/kg/day
“In vitro, taletrectinib inhibited hERG currents and hNav1.5 with IC50 values of 0.98 µM and 0.83 µM, respectively, indicating a potential effect on QT prolongation. However, in the telemetered monkey cardiovascular study, there were no effects on any electrocardiogram (ECG) parameters, including QTc at the highest non-severely toxic dose (HNSTD) of 100 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 Ibtrozi 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 in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary (FDA multi-discipline review, p. 45)
NOAEL / key findings
Target organs in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary
“Drug-related target organs in both species included lung, lymph nodes, kidney, GI tract, and pituitary.”
Risksopen answer page →
Immune & cytokine safety
Thymic atrophy and lymph node erythrophagocytosis and foamy macrophages in monkeys
“Additional findings were noted in the thymus (atrophy), lymph nodes (erythrophagocytosis, foamy macrophages), and kidneys (basophilic casts, dilation, hyperplasia, vacuolation).”
Biodistribution & persistence
Wide distribution in rats; melanin binding in eye and skin; choroid plexus accumulation, crosses the blood-brain barrier
“Taletrectinib was distributed throughout rat tissues. There was notable distribution of taletrectinib to melanin-containing tissues of the eyeball and skin. Taletrectinib also accumulated in the choroid plexus region of the brain indicating the drug can cross the blood brain barrier.”
Modality-specific risk
Embryofetal toxicity (labeled warning)
“Because taletrectinib can cause fetal harm, the review team recommends an embryofetal toxicity warning.”
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 (small molecule)
“Immunogenicity The Applicant’s Position: Not applicable. The FDA’s Assessment: Not applicable.”
Label warnings
- Hepatotoxicity
- Interstitial Lung Disease/Pneumonitis
- QTc Interval Prolongation
- Hyperuricemia
- Myalgia with Creatine Phosphokinase Elevation
- Skeletal Fractures
- Embryo-Fetal Toxicity
HepatotoxicityImmune-mediated reactionsPulmonary toxicityCardiovascularMetabolic & endocrineMusculoskeletalEmbryo-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 Ibtrozi 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 in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary (FDA multi-discipline review, p. 45)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
85-day rat and cynomolgus monkey GLP studies, each with 57-day treatment-free period
“Report 2021009: 85-Day Repeated-Dose Toxicity Study of Taletrectinib by Oral Gavage in Sprague Dawley Rats with a 57-Day Treatment-Free Period”
Pivotal GLP studies
28-day and 12-week oral studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“GLP-compliant embryo-fetal development studies were conducted in pregnant rats and rabbits to assess the effect of taletrectinib on fetal development.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal mortality and structural abnormalities at or below human exposure
“In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose”
PPND / ePPND: when
No PPND study; not typically required for advanced-cancer drugs
“though a pre‐ and postnatal development study may be capable of evaluating some of these endpoints, they are not typically required for a drug intended to treat patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies have not been conducted with taletrectinib and are not warranted for the proposed indication.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies are not planned as taletrectinib is intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required for the advanced ROS1-positive NSCLC indication
“FDA agrees that carcinogenicity studies are not warranted for the current indication of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD: pregnancy loss at lowest dose 15 mg/kg/day (0.04x human AUC); no margin
“Taletrectinib treatment resulted in increase in abortions and total pregnancy loss at doses ≥15 mg/kg/day (≥ 0.04 times the human exposure based on AUC at the recommended dose).”
NOAEL / key findings
Target organs in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary
“Drug-related target organs in both species included lung, lymph nodes, kidney, GI tract, and pituitary.”
Efficacy evidenceopen answer page →
Efficacy evidence
Subcutaneous ROS1-fusion xenografts (Ba/F3, NSCLC) and intracranial patient-derived NSCLC xenograft in mice
“Evaluation of antitumor activity was conducted in subcutaneous xenograft mouse models using Ba/F3 cells expressing ROS1 mutants/fusion proteins CD74-ROS1 and CD74-ROS1G2032R or NSCLC cells harboring the CD74-ROS1 gene fusion.”
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
No pharmacology/toxicology approvability issues; Pharm/Tox team recommends approval
“There are no approvability issues from a pharmacology/toxicology perspective. The Pharmacology/Toxicology team recommends approval of taletrectinib for NSCLC with ROS-1 mutations.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a condition
No pre- and postnatal development study despite concern for neurodevelopmental effects of Trk inhibition
Why: Not typically required for drugs treating advanced cancer; Trk-related developmental risk addressed in labeling · Within the guideline
“While embryo‐fetal development studies can detect malformations in brain structure, they are not designed to assess motor development or psychiatric function and though a pre‐ and postnatal development study may be capable of evaluating some of these endpoints, they are not typically required for a drug intended to treat patients with advanced cancer.”
“Based on this data, additional information regarding the effect of Trk inhibition on embryo-fetal development was added to the label.”
Safety marginVerdict not stated
No margin for rabbit embryo-fetal toxicity: abortions and pregnancy loss at 0.04 times human AUC
“Taletrectinib treatment resulted in increase in abortions and total pregnancy loss at doses ≥15 mg/kg/day (≥ 0.04 times the human exposure based on AUC at the recommended dose).”
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