Sephience (sepiapterin): what was done before first-in-human, and what came after?

Precedia/Small molecules/Sephience/Tox package

Sephience: what was done before first-in-human, and what came after?

sepiapterin · Tetrahydrobiopterin precursor

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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

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)

Full method, every step sourced →

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.”

✓ VerifiedEMA assessment report, p. 36Source ↗

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”

✓ VerifiedEMA assessment report, p. 34Source ↗

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).”

✓ VerifiedEMA assessment report, p. 39Source ↗

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).”

✓ VerifiedFDA integrated review, p. 146Source ↗

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.”

✓ VerifiedFDA integrated review, p. 152Source ↗

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)”

✓ VerifiedFDA integrated review, p. 138Source ↗

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.”

✓ VerifiedEMA assessment report, p. 47Source ↗

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.”

✓ VerifiedFDA integrated review, p. 139Source ↗

Summary across all 211 small molecules →

Sephience: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other small molecules