Daybue
trofinetide
Species
RatDog
Longest study
39 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 toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
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
“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
Species: general tox
Rat (4- and 26-week) and beagle dog (39-week)
“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
Species: DART
Rat and rabbit (standard reproductive and developmental battery)
“A standard battery of reproductive and developmental toxicology studies was conducted in Sprague Dawley rat and New Zealand White rabbit.”
Species: carcinogenicity
Not conducted; mouse and rat studies required postmarketing
“The nonclinical data submitted to the NDA support approval of trofinetide for the proposed indication, with appropriate labeling and post-marketing requirements for carcinogenicity studies in mouse and rat.”
Surrogate used in
No surrogate used; trofinetide tested directly
“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
Pivotal GLP studies
26-week juvenile rat and 39-week juvenile dog oral gavage studies
“The 26- and 39-week studies were conducted in juvenile animals; dosing was initiated at 2 weeks (postnatal days 13-14) and 5- 6 months of age, respectively.”
Route in tox
Oral (gavage)
“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and in vivo mouse micronucleus assays
“Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.”
Carcinogenicity
Not conducted; mouse and rat studies are postmarketing requirements
“The nonclinical data submitted to the NDA support approval of trofinetide for the proposed indication, with appropriate labeling and post-marketing requirements for carcinogenicity studies in mouse and rat.”
Reproductive & developmental
Rat and rabbit EFD: no adverse embryofetal effects
“Embryofetal development studies were conducted in rat and rabbit. Trofinetide was administered orally during the period of organogenesis at doses of 0, 150, 450, and 1000 mg/kg BID (0, 300, 900, and 2000 mg/kg/day) to rats and at doses of 0, 75, 150, and 300 mg/kg BID (0, 150, 300, and 600 mg/kg/day) to rabbits. No adverse effects on embryofetal development were observed in either species.”
Safety pharmacology
IV studies only: no rat CNS or respiratory effects; dog QTcV prolonged 19-33 ms at ≥400 mg/kg; hERG IC50 ≥20 mM
“In dogs, IV infusion of trofinetide (800 mg/kg) had no effects on heart rate or arterial blood pressure; however, the QTcV interval was slightly prolonged by 19 to 33 ms at ≥ 400 mg/kg. The IC50 value of trofinetide on hERG currents was estimated at ≥ 20 mM.”
Genotox: Ames
Negative
“Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.”
Genotox: in vivo
Mouse micronucleus: negative
“Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.”
Carcinogenicity model
Not conducted before approval (agreed with the Division)
“Carcinogenicity studies of trofinetide have not been conducted for the NDA, as previously agreed to by the division (Type C meeting minutes, June 22, 2015; email communication, November 10, 2021).”
Carcinogenicity timing
Not conducted before the marketing application (agreed with FDA); required as a postmarketing requirement
“Carcinogenicity studies have not been conducted (with agreement from the Division) prior to submission of the NDA, but these studies will be required as a PMR.”
hERG / QT
hERG IC50 ≥20 mM; dog QTcV slightly prolonged 19-33 ms at ≥400 mg/kg IV
“In dogs, IV infusion of trofinetide (800 mg/kg) had no effects on heart rate or arterial blood pressure; however, the QTcV interval was slightly prolonged by 19 to 33 ms at ≥ 400 mg/kg. The IC50 value of trofinetide on hERG currents was estimated at ≥ 20 mM.”
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 Daybue 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: Few findings; NOAELs 2000 mg/kg/day juvenile rat, 1000 (male) and 300 (female) mg/kg/day dog (uterine weight, estrus) (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Few findings; NOAELs 2000 mg/kg/day juvenile rat, 1000 (male) and 300 (female) mg/kg/day dog (uterine weight, estrus)
“These data resulted in NOAELs of 2000 mg/kg/day (1000 mg/kg BID) in juvenile rats, 1000 mg/kg/day (500 mg/kg BID) in M dogs, and 300 mg/kg/day (150 mg/kg BID) in F dogs.”
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
Widespread tissue distribution in rat, highest in GI wall, kidney and liver
“Following administration of a single oral dose of 14C-trofinetide (200 mg/kg) to male Sprague Dawley rats, tissue distribution of radioactivity was widespread, with the highest concentrations in gastrointestinal tissue (small and large intestine wall), kidney, and liver;”
Modality-specific risk
Limited exposure margins: soft feces at the high dose, with animal exposures below human exposure
“The only notable finding was an increase in watery or soft feces at the highest dose tested, which was associated with plasma exposures (AUC) less than those in pediatric and adult patients at the recommended doses.”
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
- Diarrhea
- Weight Loss
- Vomiting
Gastrointestinal
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 Daybue 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: Few findings; NOAELs 2000 mg/kg/day juvenile rat, 1000 (male) and 300 (female) mg/kg/day dog (uterine weight, estrus) (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral dog study (juvenile) with 4-week recovery
“Dog: in the 39-week (+ 4-week recovery) study, trofinetide was administered at doses of 0, 25, 150, and 500 mg/kg BID (0, 50, 300, and 1000 mg/kg/day).”
Pivotal GLP studies
26-week juvenile rat and 39-week juvenile dog oral gavage studies
“The 26- and 39-week studies were conducted in juvenile animals; dosing was initiated at 2 weeks (postnatal days 13-14) and 5- 6 months of age, respectively.”
DART package
Species: DART
Rat and rabbit (standard reproductive and developmental battery)
“A standard battery of reproductive and developmental toxicology studies was conducted in Sprague Dawley rat and New Zealand White rabbit.”
Reproductive & developmental
Rat and rabbit EFD: no adverse embryofetal effects
“Embryofetal development studies were conducted in rat and rabbit. Trofinetide was administered orally during the period of organogenesis at doses of 0, 150, 450, and 1000 mg/kg BID (0, 300, 900, and 2000 mg/kg/day) to rats and at doses of 0, 75, 150, and 300 mg/kg BID (0, 150, 300, and 600 mg/kg/day) to rabbits. No adverse effects on embryofetal development were observed in either species.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre- and postnatal development study in rat, trofinetide was administered orally throughout pregnancy and lactation at doses of 0, 150, 450, and 1000 mg/kg BID (0, 300, 900, and 2000 mg/kg/day).”
Carcinogenicity
Species: carcinogenicity
Not conducted; mouse and rat studies required postmarketing
“The nonclinical data submitted to the NDA support approval of trofinetide for the proposed indication, with appropriate labeling and post-marketing requirements for carcinogenicity studies in mouse and rat.”
Carcinogenicity model
Not conducted before approval (agreed with the Division)
“Carcinogenicity studies of trofinetide have not been conducted for the NDA, as previously agreed to by the division (Type C meeting minutes, June 22, 2015; email communication, November 10, 2021).”
Carcinogenicity timing
Not conducted before the marketing application (agreed with FDA); required as a postmarketing requirement
“Carcinogenicity studies have not been conducted (with agreement from the Division) prior to submission of the NDA, but these studies will be required as a PMR.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: 26-week rat AUC at highest dose (no adverse effects) similar to pediatric patient exposure
“No adverse effects were observed. Plasma exposure (AUC) at the highest dose tested was similar to that those in pediatric patients at recommended doses.”
NOAEL / key findings
Few findings; NOAELs 2000 mg/kg/day juvenile rat, 1000 (male) and 300 (female) mg/kg/day dog (uterine weight, estrus)
“These data resulted in NOAELs of 2000 mg/kg/day (1000 mg/kg BID) in juvenile rats, 1000 mg/kg/day (500 mg/kg BID) in M dogs, and 300 mg/kg/day (150 mg/kg BID) in F dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
MeCP2 knockout mouse model of Rett syndrome (20 mg/kg IP daily, 5 or 20 weeks)
“The pharmacology of trofinetide was characterized in in vitro and in vivo studies, including one in vivo study in an animal model of Rett syndrome (MeCP2 knockout mouse). In that study, trofinetide (0 or 20 mg/kg) was administered by intraperitoneal injection daily for 5 or 20 weeks.”
Why that model
MeCP2 knockout mouse available as an animal model of Rett syndrome; mechanism of action unknown
“The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. The pharmacology of trofinetide was characterized in in vitro and in vivo studies, including one in vivo study in an animal model of Rett syndrome (MeCP2 knockout mouse).”
Reviewer's view of the efficacy data
Limited: increased hippocampal plasticity but only trends in dendritic complexity and no effect on locomotor or respiratory function
“However, although hippocampal synaptic plasticity increased, only a trend for increased dendritic complexity and spine length was observed, and there was no effect on locomotor or respiratory functions.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; two-species carcinogenicity deferred to a postmarketing requirement
“Carcinogenicity studies have not been conducted (with agreement from the Division) prior to submission of the NDA, but these studies will be required as a PMR.”
“As previously communicated with the sponsor (correspondence dated November 10, 2021), carcinogenicity in two species will be needed but may be conducted post-approval.”
Safety pharmacologyVerdict not stated
Safety pharmacology studies done by IV bolus only, not by the clinical oral route
“Safety pharmacology studies with trofinetide were not conducted using the oral route.”
Safety marginVerdict not stated
No exposure margin in the 26-week juvenile rat study: AUC at highest dose similar to pediatric clinical exposure
“Plasma exposure (AUC) at the highest dose tested was similar to that those in pediatric patients at recommended doses.”
Impurity or metaboliteQuestioned
Impurities above the qualification threshold qualified on mg/kg margins; several not qualified when normalized to body surface area
“However, the sponsor calculated margins of the 9 impurities normalized to body weight (mg/kg) instead of normalized to body surface area (mg/m2 ). When margins are normalized to body surface area the following impurities, , are not qualified at the proposed acceptance levels.”
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