Sephience
sepiapterin
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and marmoset monkey
“repeated dose toxicity studies in rats (up to 6 months) and marmosets (up to 9 months)”
Why that species
Similar PK and metabolic profiles to humans
“Rats and marmoset monkeys were selected as the primary species for toxicology studies based on similarities in their PK and metabolic profiles to humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week in rats, sepiapterin was tested at 30, 100 and 200 mg/kg/day.”
Species: general tox
Rat (up to 6 months) and marmoset monkey (up to 9 months)
“(4) repeated dose toxicity studies in rats (up to 6 months) and marmosets (up to 9 months)”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Reproductive toxicity comprised studies on fertility and early embryonic development (rat), embryo-foetal development (rat and rabbit), pre- post-natal development (rat) and juvenile animal studies (rat).”
Species: carcinogenicity
Transgenic (Tg.rasH2) mouse, 26-week
“In the submitted 26-week transgenic mouse carcinogenicity, a group of Tg.rasH2 mice administered sepiapterin doses of 0 (Water Control)”
Surrogate used in
No surrogate used; rats and marmosets chosen for human-like PK and metabolism
“Rats and marmoset monkeys were selected as the primary species for toxicology studies based on similarities in their PK and metabolic profiles to humans.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week marmoset)
“A 39-week study was performed in marmoset monkeys with a 4-week recovery period.”
Pivotal GLP studies
GLP rat 2-, 13- and 26-week and marmoset 2-, 13- and 39-week studies
“The GLP-compliant studies in rats comprised studies with 2- 13- and 26-weeks of treatment followed by, respectively, 2- , 4- and 4- weeks recovery periods. The studies in marmoset monkeys had treatment durations of 2- 13- and 39-weeks”
Route in tox
Oral gavage
“All studies were conducted with administration of sepiapterin once a day by oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Not genotoxic overall: Ames negative; in vitro chromosome aberration positive without (not with) metabolic activation; rat micronucleus and comet negative
“Based on the weight of evidence, SEPHIENCE is not genotoxic. SEPHIENCE was negative in the Ames assay. SEPHIENCE was positive in an in vitro chromosomal aberration assay without metabolic activation but not with metabolic activation. SEPHIENCE was negative in the in vivo (micronucleus and comet) assays in rats.”
Carcinogenicity
6-month transgenic mouse study negative; 2-year bioassay not submitted
“The 2-year carcinogenicity bioassay was not included in this submission. Even though there was a negative finding in the 6-month transgenic mouse carcinogenicity study”
Reproductive & developmental
Rat EFD: no maternal or embryo-fetal toxicity up to 1000 mg/kg/day (~9-fold MRHD exposure)
“There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1000 mg/kg/day, which was the NOAEL of the study; the AUC0-24 at this dose is approximately 9-fold the exposure at the MRHD (Table 53).”
Safety pharmacology
No adverse effects; no cardiovascular effects in marmosets up to 1000 mg/kg/day
“In vivo studies in male and female marmoset monkeys showed no cardiovascular effects at doses up to 1000 mg/kg/day. Overall, no sepiapterin-related adverse effects were observed in these safety pharmacology studies.”
Genotox: Ames
Negative
“CNSA-001 (sepiapterin) was not mutagenic in the Ames test, the in vivo micronucleus (MN), and Comet assays in rats (Table 61).”
Genotox: in vitro mammalian
Positive in vitro chromosome aberration test without S9 (3 h and 20 h)
“However, CNSA-001 showed a positive response in vitro chromosome aberration test at 3hr and 20hr treatment without S9.”
Genotox: in vivo
Negative rat in vivo micronucleus and Comet assays
“CNSA-001 (sepiapterin) was not mutagenic in the Ames test, the in vivo micronucleus (MN), and Comet assays in rats (Table 61).”
Carcinogenicity model
26-week Tg mouse study: no carcinogenic effect at any dose
“Sepiapterin was administrated for 26 weeks in Tg mice at dose of 30, 100 and 300 mg/kg/day in males and 100, 300 and 1000 mg/kg/day in females. No carcinogenic effect related to sepiapterin administration was observed at any dose level in males or females in this study.”
Carcinogenicity timing
26-week Tg.rasH2 mouse completed; 2-year rat study required after approval (PMR)
“Therefore, a postmarketing requirement for a 2-year carcinogenicity study in rats to evaluate the carcinogenicity risk is warranted.”
hERG / QT
No hERG effect at 30 µM, 2978× the free Cmax at 60 mg/kg/day
“Sepiapterin had no discernible effects at the highest tested concentration of 30 µM (or approximately 7117 ng/mL, which is 2978× the mean sepiapterin free Cmax of 2.39 ng/mL at the highest targeted therapeutic dose of 60 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 Sephience 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: 26-week rat NOAEL 30 mg/kg/day (1.5-fold human exposure); adverse kidney findings at 100 and 200 mg/kg/day (FDA integrated review, p. 101)
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day (1.5-fold human exposure); adverse kidney findings at 100 and 200 mg/kg/day
“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”
Risksopen answer page →
Immune & cytokine safety
No immune-system effects in repeat-dose studies; no immunotoxicity studies
“No immunotoxicity assessments were performed as no sepiapterin-related effects on the immune system were observed in repeat-dose mammalian toxicology studies.”
Biodistribution & persistence
Low, non-retained distribution to melanin-containing tissues (meninges, uveal tract); no melanin association
“Distribution of radioactivity to certain melanin-containing tissues, such as the meninges and uveal tract was low and there was no extended retention, indicating that [14C]-sepiapterin-derived radioactivity was most likely not associating with melanin in these tissues.”
Modality-specific risk
Dose-related reversible and non-reversible kidney toxicity in rat repeat-dose studies
“Dose-related reversible and non-reversible kidney toxicities were the main clinically relevant nonclinical safety signal identified from the rat repeat dose toxicity studies.”
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
- Increased Bleeding
- Hypophenylalaninemia
- Interaction with Levodopa
Bleeding
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 Sephience 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: 26-week rat NOAEL 30 mg/kg/day (1.5-fold human exposure); adverse kidney findings at 100 and 200 mg/kg/day (FDA integrated review, p. 101)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week marmoset monkey (oral) with 4-week recovery
“A 39-week study was performed in marmoset monkeys with a 4-week recovery period.”
Pivotal GLP studies
GLP rat 2-, 13- and 26-week and marmoset 2-, 13- and 39-week studies
“The GLP-compliant studies in rats comprised studies with 2- 13- and 26-weeks of treatment followed by, respectively, 2- , 4- and 4- weeks recovery periods. The studies in marmoset monkeys had treatment durations of 2- 13- and 39-weeks”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Reproductive toxicity comprised studies on fertility and early embryonic development (rat), embryo-foetal development (rat and rabbit), pre- post-natal development (rat) and juvenile animal studies (rat).”
Reproductive & developmental
Rat EFD: no maternal or embryo-fetal toxicity up to 1000 mg/kg/day (~9-fold MRHD exposure)
“There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1000 mg/kg/day, which was the NOAEL of the study; the AUC0-24 at this dose is approximately 9-fold the exposure at the MRHD (Table 53).”
PPND / ePPND: when
Rat PPND completed for the marketing application after FDA refused a waiver
“The Agency provided a response on January 30, 2023, conveying their disagreement with the request and stating that a pre- and post-natal developmental study to assess postnatal effects following in utero and lactational exposure would be needed to support a marketing application.”
Carcinogenicity
Species: carcinogenicity
Transgenic (Tg.rasH2) mouse, 26-week
“In the submitted 26-week transgenic mouse carcinogenicity, a group of Tg.rasH2 mice administered sepiapterin doses of 0 (Water Control)”
Carcinogenicity model
26-week Tg mouse study: no carcinogenic effect at any dose
“Sepiapterin was administrated for 26 weeks in Tg mice at dose of 30, 100 and 300 mg/kg/day in males and 100, 300 and 1000 mg/kg/day in females. No carcinogenic effect related to sepiapterin administration was observed at any dose level in males or females in this study.”
Carcinogenicity timing
26-week Tg.rasH2 mouse completed; 2-year rat study required after approval (PMR)
“Therefore, a postmarketing requirement for a 2-year carcinogenicity study in rats to evaluate the carcinogenicity risk is warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat NOAEL 30 mg/kg/day, 1.5-fold human exposure at MRHD (kidney findings above)
“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day (1.5-fold human exposure); adverse kidney findings at 100 and 200 mg/kg/day
“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”
Efficacy evidenceopen answer page →
Efficacy evidence
Pah-R261Q PKU mouse (single dose) plus COS-7 cells expressing PAH variants
“The potential effectiveness of sepiapterin was evaluated in three in vitro studies using COS-7 cells expressing different PAH protein variants and an in vivo single dose non-GLP study with a Pah-R261Q mouse model of human PKU disease.”
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
FDA: studies have limitations; in vitro non-GLP data insufficient to define the dual mechanism
“These studies have limitations in supporting sepiapterin effectiveness and mechanism of action. The in vitro non-GLP studies are not sufficient to clearly define a dual mechanism for sepiapterin.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No 2-year rat carcinogenicity study before approval; weight-of-evidence waiver refused and study deferred to a postmarketing requirement
Why: PKU causes significant morbidity with high unmet medical need, so the 2-year study is a postmarketing requirement rather than pre-approval · Rare disease / unmet need · Serious disease
“PTC also requested a carcinogenicity waiver on March 20, 2023. Following a review of PTC’s weight of evidence document which was proposed in lieu of conducting a 2-year rat carcinogenicity study, the Agency informed PTC on June 2, 2023, that the neoplastic and preneoplastic findings observed with sepiapterin in rats necessitated a 2-year rat carcinogenicity study.”
“Because PKU causes significant morbidity, and patients with PKU face substantial health complications, which leads to care and social burden and the high unmet medical need, the 2-year carcinogenicity study will not be required prior to approval but will be a post-marketing requirement study.”
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