Nereus
tradipitant
Species
RatMouseDog
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (plus 13-week mouse)
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months).”
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
“In a 6-month toxicity study in Fischer 344 rats, tradipitant was orally administered once daily at doses of 0 (vehicle), 15, 150, or 1500 mg/kg/day.”
Species: general tox
Mouse (13 weeks), rat (up to 6 months) and dog (up to 3 months)
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months).”
Species: DART
Rat (dosing during organogenesis through lactation) and rabbit (organogenesis)
“In animal reproduction studies, no adverse developmental effects were observed with oral administration of tradipitant to pregnant rats during organogenesis through lactation or to pregnant rabbits during organogenesis at doses up to approximately 3.3 and 1.4 times the exposure to tradipitant at the maximum recommended human dose (MRHD), respectively.”
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Han Wistar rat (104-week)
“The carcinogenic potential of tradipitant was evaluated in a 26-week study in CB6F1-TgN (RasH2) transgenic mice and a 104-week study in Han Wistar rats.”
Surrogate used in
No surrogate used
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months).”
Study lengthopen answer page →
Longest pivotal study
26 (6-month rat)
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months).”
Pivotal GLP studies
6-month Fischer rat, 3-month Han Wistar rat and 3-month dog studies
“repeat-dose toxicity studies in mice (13 weeks), Fisher rats (1, 3, and 6 months), Han Wistar rats (3 months), and dogs (1 and 3 months)”
Route in tox
Oral
“In a 6-month toxicity study in Fischer 344 rats, tradipitant was orally administered once daily at doses of 0 (vehicle), 15, 150, or 1500 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and mouse micronucleus assays
“Tradipitant was negative in a complete battery of genetic toxicity studies, including the Ames assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo micronucleus assay in mice.”
Carcinogenicity
26-week rasH2 mouse: no tumors; 2-year rat: dose-related thyroid follicular cell tumors at all doses
“In transgenic rasH2 mice orally administered tradipitant (15, 50, or 1500 mg/kg/day) for 26 weeks, there was no increase in tumors. In rats orally administered tradipitant (10, 30, or 150 mg/kg/day) for at least 104 weeks, a dose- related increase in the incidence of thyroid follicular cell tumors (adenomas or adenomas combined with carcinomas), correlating with the findings of thyroid masses and cysts, was observed at all tested doses”
Reproductive & developmental
Rat combined fertility/EFD: no effects on fertility, maternal health or embryo-fetal development up to 1000 mg/kg/day
“No effects on fertility, maternal health, or embryo-fetal development were observed in rats treated with tradipitant during the periods of mating and organogenesis at doses up to 1000 mg/kg/day (57-fold the maximum clinical dose, based on HED; 2.2-fold based on AUC).”
Safety pharmacology
No ECG effects in conscious dogs at single oral doses up to 800 mg/kg (157-fold clinical dose)
“In a cardiovascular safety pharmacology study in conscious male and female Beagle dogs, single oral doses of tradipitant up to 800 mg/kg had no significant effects on qualitative or quantitative ECG parameters (157-fold the maximum clinical dose of 170 mg, based on HED).”
Genotox: Ames
Negative
“Tradipitant was negative in a complete battery of genetic toxicity studies, including the Ames assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo micronucleus assay in mice.”
Genotox: in vitro mammalian
Chromosomal aberration in human lymphocytes: negative
“Tradipitant was negative in a complete battery of genetic toxicity studies, including the Ames assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo micronucleus assay in mice.”
Genotox: in vivo
Mouse micronucleus: negative
“Tradipitant was negative in a complete battery of genetic toxicity studies, including the Ames assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo micronucleus assay in mice.”
Carcinogenicity model
26-week Tg rasH2 mouse (no tumors up to 1500 mg/kg/day); 104-week Han Wistar rat
“The carcinogenic potential of tradipitant was evaluated in a 26-week study in CB6F1-TgN (RasH2) transgenic mice and a 104-week study in Han Wistar rats. In transgenic mice, no tumors were attributed to treatment with tradipitant at doses up to 1500 mg/kg/day.”
Carcinogenicity timing
6-month transgenic mouse and 2-year rat completed and submitted to the IND before the marketing application
“the 6-month carcinogenicity study in transgenic mice, and the 2-year carcinogenicity study in rats were submitted to IND 141315.”
hERG / QT
hERG IC50 3.91 μM (2,299 ng/mL), about 27-, 21- and 7.0-fold clinical Cmax; significant inhibition
“Tradipitant significantly inhibited the hERG channel current in vitro, with an IC50 value of 3.91μM (2,299 ng/mL; approximately 27-, 21-, and 7.0-fold the clinical Cmax”
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 Nereus 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Target organs liver and thyroid (FDA integrated review, p. 107)
NOAEL / key findings
Target organs liver and thyroid
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months). Target organs were identified as liver and thyroid.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Excreted in milk of lactating rats
“Tradipitant was excreted in milk of lactating rats that received tradipitant at 100, 300, or 1000 mg/kg (2.3, 2.4, and 3.3 times the exposure to tradipitant at the MRHD) during pregnancy from gestation day 6 through lactation day 20.”
Modality-specific risk
Hepatotoxicity: liver injury risk from tradipitant and its major metabolites
“Based on the available nonclinical data, a risk for liver injury with tradipitant and its major metabolites has been identified.”
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
- Effects on the Ability to Drive or Operate Machinery
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 Nereus 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Target organs liver and thyroid (FDA integrated review, p. 107)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Fischer rat (oral; longest repeat-dose study) with recovery period
“Considering that all findings were resolved following the recovery period, no other histopathological findings indicative of hepatic or renal injury were observed, and there were no findings indicative of renal function impairment, the toxicological significance of the liver, thyroid, and kidney findings was considered limited.”
Pivotal GLP studies
6-month Fischer rat, 3-month Han Wistar rat and 3-month dog studies
“repeat-dose toxicity studies in mice (13 weeks), Fisher rats (1, 3, and 6 months), Han Wistar rats (3 months), and dogs (1 and 3 months)”
DART package
Species: DART
Rat (dosing during organogenesis through lactation) and rabbit (organogenesis)
“In animal reproduction studies, no adverse developmental effects were observed with oral administration of tradipitant to pregnant rats during organogenesis through lactation or to pregnant rabbits during organogenesis at doses up to approximately 3.3 and 1.4 times the exposure to tradipitant at the maximum recommended human dose (MRHD), respectively.”
Reproductive & developmental
Rat combined fertility/EFD: no effects on fertility, maternal health or embryo-fetal development up to 1000 mg/kg/day
“No effects on fertility, maternal health, or embryo-fetal development were observed in rats treated with tradipitant during the periods of mating and organogenesis at doses up to 1000 mg/kg/day (57-fold the maximum clinical dose, based on HED; 2.2-fold based on AUC).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“a complete battery of reproductive toxicity studies including a combined fertility, early embryonic development, and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and a pre- and postnatal development study in rats”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Han Wistar rat (104-week)
“The carcinogenic potential of tradipitant was evaluated in a 26-week study in CB6F1-TgN (RasH2) transgenic mice and a 104-week study in Han Wistar rats.”
Carcinogenicity model
26-week Tg rasH2 mouse (no tumors up to 1500 mg/kg/day); 104-week Han Wistar rat
“The carcinogenic potential of tradipitant was evaluated in a 26-week study in CB6F1-TgN (RasH2) transgenic mice and a 104-week study in Han Wistar rats. In transgenic mice, no tumors were attributed to treatment with tradipitant at doses up to 1500 mg/kg/day.”
Carcinogenicity timing
6-month transgenic mouse and 2-year rat completed and submitted to the IND before the marketing application
“the 6-month carcinogenicity study in transgenic mice, and the 2-year carcinogenicity study in rats were submitted to IND 141315.”
Safety marginopen answer page →
Safety margin at NOAEL
Han Wistar rat repeat-dose study (liver necrosis): male NOAEL 15 mg/kg/day below maximum clinical dose (HED); female NOAEL 8.5-fold
“Based on the adverse findings of necrosis in the liver of males at ≥150 mg/kg/day and females at 1500 mg/kg/day, the NOAEL was considered the lowest dose of 15 mg/kg/day in males (less than the maximum clinical dose, based on HED) and the mid dose of 150 mg/kg/day in females (8.5-fold the maximum clinical dose)”
NOAEL / key findings
Target organs liver and thyroid
“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months). Target organs were identified as liver and thyroid.”
Efficacy evidenceopen answer page →
Efficacy evidence
Apomorphine-induced emesis in Beagle dogs (single oral dose reduced emesis incidence)
“In a study in male Beagle dogs, a single oral dose of tradipitant at 0.3, 1.0, or 3.0 mg/kg (less than the clinical dose of tradipitant of 170 mg/day, based on human equivalent dose [HED]) administered 2 hours prior to challenge with the pro-emetogenic drug, apomorphine, resulted in significantly decreased incidence of emesis compared to no treatment.”
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
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.
Flexibilityopen answer page →
Flexibility accepted
Study lengthAccepted with a conditionBeyond the letter
No ≥6-month nonrodent toxicity study for unrestricted, repeated intermittent lifetime use; dog studies subchronic only
Why: No sufficient justification; approved with label stating safety not established beyond 90 total doses · Human data
“However, the Applicant did not submit a ≥6-month toxicity study in a nonrodent species and did not provide sufficient scientific justification for why such a study was not warranted to support the safety of unrestricted use of tradipitant over a lifetime for this indication.”
“Based on the available safety data, tradipitant is recommended for approval with a description in the label that the safety of tradipitant has not been established for more than 90 total doses to adequately inform prescribers of the safe use of tradipitant.”
Impurity or metaboliteAcceptedBeyond the letter
Disproportionate human metabolites M2, M4 and M8 not qualified in animals; qualified by weight of evidence on total drug-related exposure
Why: WoE (structural evaluation, on- and off-target effects) shows no increased or novel toxicities versus tradipitant · Weight of evidence
“Metabolite M3 is the only metabolite qualified by the levels present in the nonclinical studies, while M2, M4, and M8 were not measured, not present, or present at low levels in animals and therefore not considered qualified for safety using typical approaches.”
“However, M2, M4, and M8 are not likely to produce increased or novel toxicities compared to tradipitant, based on a Weight of Evidence (WoE) analysis including structural evaluations and assessment of known on- and off-target effects of tradipitant and the metabolites.”
GLPQuestioned
Four-organ microphysiological system studies offered in lieu of chronic nonrodent study were not GLP-compliant
“The lack of U.S. FDA GLP compliance and absence of adequate justification by the Applicant for noncompliance are considered limitations of these studies.”
Safety marginVerdict not stated
Han Wistar rat male NOAEL (liver necrosis) below the maximum clinical dose on an HED basis
“Based on the adverse findings of necrosis in the liver of males at ≥150 mg/kg/day and females at 1500 mg/kg/day, the NOAEL was considered the lowest dose of 15 mg/kg/day in males (less than the maximum clinical dose, based on HED) and the mid dose of 150 mg/kg/day in females (8.5-fold the maximum clinical dose)”
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