Azstarys
serdexmethylphenidate and dexmethylphenidate
Species
RatDogRabbit
Longest study
26 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 (28-day); rabbit (6-month juvenile, EFD)
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Why that species
Rabbit chosen by cross-species PK analysis as having the highest SDX exposure relative to humans (minimizing d-MPH exposure)
“In order to use the species with the highest SDX exposure compared to humans in the pivotal embryo-fetal development study and the 6-month juvenile animal study, a cross-species analysis was conducted, and the rabbit was determined to be the most appropriate species.”
Surrogate molecule
No surrogate; the clinical compound (SDX) was tested, with d-MPH as comparator
“In rat and dog single- and repeat-dose toxicology studies of up to 28-day duration of oral SDX with d-MPH as a comparator”
Species: general tox
Rat and dog (28-day); juvenile rabbit (6-month)
“there were no unique, adverse findings for SDX compared to d-MPH in 28-day repeat-dose toxicology studies in rat and dog, embryo-fetal development study in rabbits, and 6-month juvenile animal study in rabbits”
Species: DART
Rabbit only (EFD and 6-month juvenile study)
“there were no unique, adverse findings for SDX compared to d-MPH in 28-day repeat-dose toxicology studies in rat and dog, embryo-fetal development study in rabbits, and 6-month juvenile animal study in rabbits”
Species: carcinogenicity
Not conducted with SDX; relies on referenced d-MPH labeling
“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”
Surrogate used in
No surrogate used; SDX tested directly with d-MPH as comparator
“In rat and dog single- and repeat-dose toxicology studies of up to 28-day duration of oral SDX with d-MPH as a comparator”
Study lengthopen answer page →
Longest pivotal study
26 (6-month juvenile rabbit)
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Pivotal GLP studies
28-day rat and dog studies and 6-month juvenile rabbit study
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Route in tox
Oral (gavage / stomach tube)
“A 6-Month Study of KP415 Administered by Oral (Stomach Tube) Administration in Juvenile Rabbits with a 1-Month Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus, in vivo rat bone marrow micronucleus and rat comet assays
“Serdexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mammalian cell micronucleus assay using human peripheral blood lymphocytes, in the in vivo rat bone barrow micronucleus assay, or in the in vivo rat alkaline comet assay.”
Carcinogenicity
Not conducted with SDX; relies on referenced d-MPH (Focalin XR) labeling
“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”
Reproductive & developmental
Rabbit EFD: no maternal or fetal developmental toxicity up to 49x MRHD (400 mg/kg)
“In the embryo-fetal development study in rabbits, there were no findings of maternal or fetal development toxicity at exposures up to 49 times (400 mg/kg) the MRHD.”
Safety pharmacology
CNS, hERG, cardiovascular and respiratory battery: stimulant-type effects comparable to d-MPH; hERG IC50 >25 uM
“All findings for SDX were typical of a CNS stimulant (including dilated pupil, increased activity, increased heart rate and blood pressure, and increased respiratory rate) and all findings were generally comparable for SDX and a comparative dose of d-MPH. In the hERG assay, the IC50 for SDX was considered >25 µM.”
Genotox: Ames
Negative
“SDX was negative for mutagenicity in bacterial cells in a valid Ames assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: negative
“SDX was negative for clastogenicity in human lymphocytes in a valid in vitro micronucleus assay.”
Genotox: in vivo
Rat micronucleus and Comet assay: negative up to 100 mg/kg
“SDX was not clastogenic in a valid in vivo micronucleus assay and Comet assay up to a dose of 100 mg/kg.”
Carcinogenicity model
Not conducted; rodents not relevant due to species PK differences; relies on d-MPH data
“In addition, carcinogenicity studies in mice or rats, fertility and early embryonic development in rats, embryofetal development in rats, and prenatal and postnatal development study in rats would not be informative because of species differences in pharmacokinetics for SDX”
Carcinogenicity timing
Not needed (weight of evidence; prodrug of approved d-MPH); relies on referenced labeling
“Therefore, considering the weight-of-evidence, we agree that carcinogenicity studies are not needed for SDX.”
hERG / QT
hERG IC50 >25 µM
“In the hERG assay, the IC50 for SDX was considered >25 µM.”
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 Azstarys 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: Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose (FDA multi-discipline review, p. 45)
NOAEL / key findings
Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose
“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”
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
Wide distribution in rat; highest in eye uvea, kidney, liver, gastric mucosa and small intestine
“[14C]SDX-related radioactivity widely distributed in rat tissues with the highest radioactivity concentrations observed in eye uvea, kidney cortex and medulla, liver, gastric mucosa of stomach, and small intestine.”
Modality-specific risk
New prodrug with longer human half-life and species PK differences: need to exclude SDX-unique toxicity vs d-MPH, chronic/juvenile toxicity
“However, even though SDX is a prodrug of an approved product (d-MPH), we determined that a chronic study adequately assessing SDX toxicity in an appropriate species was needed because SDX is an NME that has a longer half-life in humans (~5.7 hours) compared to other species (~0.5-2 hours).”
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
Boxed warning: Abuse, misuse, and addiction
- Abuse, Misuse, and Addiction
- Risks to Patients with Serious Cardiac Disease
- Increased Blood Pressure and Heart Rate
- Psychiatric Adverse Reactions
- Priapism
- Peripheral Vasculopathy, including Raynaud's Phenomenon
- Long-Term Suppression of Growth in Pediatric Patients
- Acute Angle Closure Glaucoma
- Increased Intraocular Pressure and Glaucoma
- Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
PsychiatricCardiovascularOcular toxicity
US prescribing information, Boxed Warning and 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 Azstarys 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: Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose (FDA multi-discipline review, p. 45)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month juvenile rabbit (oral gavage) with 1-month recovery
“A 6-Month Study of KP415 Administered by Oral (Stomach Tube) Administration in Juvenile Rabbits with a 1-Month Recovery Period/Study No. 20144952”
Pivotal GLP studies
28-day rat and dog studies and 6-month juvenile rabbit study
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
DART package
Species: DART
Rabbit only (EFD and 6-month juvenile study)
“there were no unique, adverse findings for SDX compared to d-MPH in 28-day repeat-dose toxicology studies in rat and dog, embryo-fetal development study in rabbits, and 6-month juvenile animal study in rabbits”
Reproductive & developmental
Rabbit EFD: no maternal or fetal developmental toxicity up to 49x MRHD (400 mg/kg)
“In the embryo-fetal development study in rabbits, there were no findings of maternal or fetal development toxicity at exposures up to 49 times (400 mg/kg) the MRHD.”
PPND / ePPND: when
PPND not conducted with serdexmethylphenidate; relies on referenced d-MPH labeling
“A pre- and postnatal development study was not conducted with SDX. As noted above, further studies to characterize the effect of SDX and unique metabolites were not deemed warranted”
Carcinogenicity
Species: carcinogenicity
Not conducted with SDX; relies on referenced d-MPH labeling
“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”
Carcinogenicity model
Not conducted; rodents not relevant due to species PK differences; relies on d-MPH data
“In addition, carcinogenicity studies in mice or rats, fertility and early embryonic development in rats, embryofetal development in rats, and prenatal and postnatal development study in rats would not be informative because of species differences in pharmacokinetics for SDX”
Carcinogenicity timing
Not needed (weight of evidence; prodrug of approved d-MPH); relies on referenced labeling
“Therefore, considering the weight-of-evidence, we agree that carcinogenicity studies are not needed for SDX.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: rat NOAEL (25 mg/kg) exposure below human exposure at MRHD
“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD.”
NOAEL / key findings
Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose
“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro radioligand binding only: SDX showed no significant binding to human DAT, NET or SERT
“In a primary pharmacology in vitro radioligand receptor binding assay (Study No. AB54825); SDX at concentrations from 0.03 to 10 µM did not show significant binding to the human dopamine transporter (DAT), norepinephrine transporter (NET), or serotonin transporter”
Why that model
SDX is a prodrug of the previously approved d-MPH
“KP415 is a combination of a new molecular entity (NME), serdexmethylphenidate (SDX), and a previously approved product, dexmethylphenidate (d-MPH). SDX is a prodrug of d-MPH.”
Reviewer's view of the efficacy data
FDA: SDX has no pharmacological activity at monoamine transporters or 68 other targets and low oral bioavailability
“SDX has low oral bioavailability in humans (<3%), has no pharmacological activity at serotonin, dopamine, or norepinephrine transporters or 68 other molecular targets examined, and is not genotoxic in a battery of assays.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
Abbreviated program for an NME: 28-day repeat-dose studies in rat and dog only; no chronic adult toxicity studies
Why: No unique adverse findings for SDX compared to d-MPH in the 28-day rat and dog studies · Weight of evidence
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
“Upon review, it was concluded that additional nonclinical studies are not needed for SDX because there were no unique, adverse findings for SDX compared to d-MPH in 28-day repeat-dose toxicology studies in rat and dog”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for an NME with a chronic indication; relies on referenced d-MPH labeling
Why: Prodrug of approved d-MPH releasing MPH and endogenous or dietary products; weight of evidence · Weight of evidence · Pharmacology or kinetics
“Typically, an NME for a chronic indication would require carcinogenicity studies in two species. However, SDX is a prodrug for an approved product (d-MPH) that predominantly releases MPH and other products that are either found endogenously and/or obtained in diet at levels greater than what will be released at the MRHD.”
“Therefore, considering the weight-of-evidence, we agree that carcinogenicity studies are not needed for SDX.”
DARTAcceptedBeyond the letter
No fertility/early embryonic or pre- and postnatal development studies; embryo-fetal study in rabbit only
Why: No unique toxicities in embryo-fetal and chronic juvenile studies; referenced d-MPH labeling · Weight of evidence
“Fertility and early embryonic development studies were not conducted with SDX. The Applicant is relying upon the developmental toxicity data in the referenced product labeling.”
“Based on results from the embryo-fetal development and chronic juvenile animal studies, we agree that fertility and early embryonic development and prenatal and postnatal development studies do not need to be conducted with SDX.”
Juvenile toxAcceptedBeyond the letter
Pivotal chronic juvenile toxicity study conducted in rabbit, a non-conventional juvenile species
Why: Testing in a species that minimizes d-MPH exposure allows adequate SDX doses with high margins · Pharmacology or kinetics
“Although rabbit is not a conventional species for a juvenile animal study, we agree that it is the most appropriate species for the two pivotal studies (rabbit is typically used for embryo-fetal development).”
“In addition, because d-MPH-related clinical signs are dose-limiting in animals and already known (both for animals and humans), testing SDX in a species that minimizes d-MPH exposure is also needed in order to test adequate SDX doses that provide high margins to human doses.”
Safety marginVerdict not stated
Rat NOAEL exposure below human exposure at the MRHD; dog NOAEL not established
“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”
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