Augtyro
repotrectinib
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 repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Why that species
100% sequence homology of target binding sites with human and similar metabolism
“Rats (Sprague-Dawley) and monkeys (cynomolgus) are considered relevant toxicological species based on 100% sequence homology for the target binding sites and similar metabolism.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Species: general tox
Rat and cynomolgus monkey (28-day and 91-day oral)
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Species: DART
Rat (dose-range-finding EFD)
“Reproductive and developmental toxicology assessment of repotrectinib included a dose range finding embryofetal development study in female rats with orally administered repotrectinib.”
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Surrogate used in
No surrogate used; repotrectinib tested directly
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
13 (91-day rat and monkey)
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Pivotal GLP studies
28-day and 91-day oral GLP studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Route in tox
Oral
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; genotoxic via aneugenic mechanism in vitro (TK6 cells) and in vivo rat bone marrow micronucleus assay
“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.”
Carcinogenicity
Not conducted; not warranted for the advanced cancer indication
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Reproductive & developmental
Rat EFD: malrotated hindlimbs and lower fetal weights at ≥12 mg/kg; maternal skin lesions at ≥6 mg/kg
“In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg”
Safety pharmacology
No cardiovascular effects in monkeys or on hERG, Nav1.5 and Cav1.2 channels; no respiratory effects in rats or monkeys
“Repotrectinib had no toxicologically significant effects on cardiovascular function in vivo in monkeys or in vitro on hERG, hNaV1.5, or hCaV1.2 channels. Repotrectinib had no effect on respiratory function rats and monkeys.”
Genotox: Ames
Negative
“Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
In vitro micronucleus (human TK6 cells): positive, aneugenic
“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action.”
Genotox: in vivo
Rat bone marrow micronucleus: positive in males at ≥500 mg/kg
“In vivo, repotrectinib was positive for genotoxicity in male rats for micronucleated polychromatic erythrocytes (PCEs) in bone marrow at doses ≥500 mg/kg.”
Carcinogenicity model
Not conducted (not warranted for the indication)
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Carcinogenicity timing
Not required for the advanced cancer indication
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
hERG / QT
hERG IC50 18 µM, 196-fold unbound Cmax (0.092 µM)
“Cmax of unbound repotrectinib was calculated by the FDA clinical and nonclinical team to be 0.092 µM, thus the 18 µM IC50 for hERG channel inhibition corresponds to a 196-fold multiple.”
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 Augtyro 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: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible (EMA assessment report, p. 30)
NOAEL / key findings
Target organs: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible
“In the pivotal GLP-compliant RD-toxicity studies, the major target organs across species were the skin (rat), CNS (rat), bone marrow (rat and monkey), and GI (monkey). These findings were generally dose-dependent and were reversible or showed a trend towards reversibility.”
Risksopen answer page →
Immune & cytokine safety
Non-adverse decreased lymphocytes in blood and lymphoid organs in rats and monkeys
“In rats, non-adverse decreased lymphocytes in circulation and in multiple lymphoid organs were observed at ≥15 mg/kg (M) and at ≥5 mg/kg (F).”
Biodistribution & persistence
Wide distribution, highest in pigmented skin, uveal tract, liver and kidney; low CNS penetration
“The distribution of repotrectinib was widespread by 1 hour post-dose with the highest exposures in pigmented skin, uveal tract, liver, renal cortex, and kidneys with low distribution into non-circumventricular CNS tissue (protected by blood-brain barrier).”
Modality-specific risk
CNS toxicity (ataxia, tremors), possibly related to TRK inhibition
“CNS toxicity observed in animal studies with repotrectinib may be related to inhibition of TRK proteins.”
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 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.
Label warnings
- Central Nervous System Adverse Reactions
- Interstitial Lung Disease/Pneumonitis
- Hepatotoxicity
- Myalgia with Creatine Phosphokinase Elevation
- Hyperuricemia
- Skeletal Fractures
- Embryo-Fetal Toxicity
NeurotoxicityImmune-mediated reactionsPulmonary toxicityHepatotoxicityMusculoskeletalMetabolic & endocrineEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not named: international first-in-human dose escalation and expansion study (TRIDENT-1) in patients with advanced solid tumors
“The recommendation for traditional approval is based on the results from TRIDENT-1, an international, single-arm, first-in-human, dose escalation and expansion study of repotrectinib in patients with advanced solid tumors with ALK, ROS1, or NTRK1-2 rearrangements.”
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 Augtyro 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: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
91-day oral monkey study with 28-day recovery (91-day rat study of the same design)
“TPX-0005: A 91-Day Oral Toxicity Study in Monkeys with a 28-Day Recovery Period”
Pivotal GLP studies
28-day and 91-day oral GLP studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
DART package
Species: DART
Rat (dose-range-finding EFD)
“Reproductive and developmental toxicology assessment of repotrectinib included a dose range finding embryofetal development study in female rats with orally administered repotrectinib.”
Reproductive & developmental
Rat EFD: malrotated hindlimbs and lower fetal weights at ≥12 mg/kg; maternal skin lesions at ≥6 mg/kg
“In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg”
PPND / ePPND: when
Not conducted or planned, per ICH S9 (advanced cancer)
“No fertility, early embryonic, prenatal, or postnatal development studies have been conducted nor are any planned with repotrectinib in accordance with ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Carcinogenicity model
Not conducted (not warranted for the indication)
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Carcinogenicity timing
Not required for the advanced cancer indication
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL: low to non-existing safety margins vs clinical exposure at 160 mg BID
“Major target organs for toxicity in rats comprises CNS, skin and bone marrow, with low to non-existing safety margins based on systemic exposure at NOAEL and expected human exposure at clinical intended dosing of 160 mg BID.”
NOAEL / key findings
Target organs: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible
“In the pivotal GLP-compliant RD-toxicity studies, the major target organs across species were the skin (rat), CNS (rat), bone marrow (rat and monkey), and GI (monkey). These findings were generally dose-dependent and were reversible or showed a trend towards reversibility.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse subcutaneous allograft/xenograft tumors (engineered NIH/3T3 or Ba/F3 cells expressing ROS1 mutants/fusions)
“Cell lines such as NIH/3T3 cells, a murine fibroblast cell line, or Ba/F3 cells, a murine pro-B cell line, were engineered to express ROS1 mutants/fusion proteins for xenograft studies.”
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
Antitumor activity shown only in subcutaneous xenografts; no NSCLC or patient-derived NSCLC cell lines
“Evaluation of antitumor activity was conducted in subcutaneous xenograft models and did not include NSCLC cell lines or patient derived NSCLC cell lines.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Only a non-GLP dose-range-finding rat EFD study; no definitive EFD study
Why: Preliminary study already showed potentially teratogenic effects; consistent with ICH S9 Q&A and ICH S5(R3) · Within the guideline
“The foetal effects indicated potentially teratogenic effects, hence no definitive EFD studies were conducted, which is supported and consistent with relevant guidelines (ICH S9 Q&A document 2018 and ICH S5 (R3) 2020).”
Safety pharmacologyAccepted
hERG assay not GLP-compliant; no dedicated GLP safety pharmacology studies
Why: Dedicated safety studies not warranted under ICH S9; ECG measurements in non-rodents considered sufficient · Within the guideline
“Although, the hERG assay was not GLP-compliant, no additional study is required as no dedicated safety studies are warranted according to ICH S9 guideline, and appropriate and ECG measurements in non-rodents are generally considered sufficient.”
Safety marginVerdict not stated
Low to non-existing exposure margins at rat NOAEL for CNS, skin and bone marrow toxicity versus 160 mg BID
“Major target organs for toxicity in rats comprises CNS, skin and bone marrow, with low to non-existing safety margins based on systemic exposure at NOAEL and expected human exposure at clinical intended dosing of 160 mg BID.”
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