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.”
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.”
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.”