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

Precedia/Small molecules/Blujepa/Tox package

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

gepotidacin · Bacterial topoisomerases (gyrase/topo IV)

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 Blujepa 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: Kidney: tubular basophilia and dilation in 4-week rat at ≥450 mg/kg/day, about the clinical exposure (FDA integrated review, p. 67)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week rat (oral gavage) with 28-day recovery; 13-week dog of equal length also had recovery groups

“Study #2013N160007 /GSK2140944E: A 13-week Oral (Gavage) Toxicity in Rats Followed by a 28-day Recovery Period”

✓ VerifiedFDA integrated review, p. 126Source ↗

Pivotal GLP studies

13-week rat and 13-week dog repeat-dose studies

“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”

✓ VerifiedFDA integrated review, p. 66Source ↗

DART package

Species: DART

Mouse and rat (EFD); mouse (pre- and postnatal development)

“In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures less than the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures approximately equal to the MRHD”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Mouse and rat EFD: decreased fetal weight and late resorptions below clinical exposure; mouse pre/postnatal study: no adverse effects

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

PPND in mouse (oral) completed before the marketing application

“In a pre- and postnatal development mouse study, 0 (vehicle), 200, 500, or 1000 mg/kg/day gepotidacin was administered by oral gavage to female mice from GD6 to lactation day 20 (LD20).”

✓ VerifiedFDA integrated review, p. 105Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“Long term carcinogenicity studies have not been conducted with gepotidacin.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Not conducted

“Long term carcinogenicity studies have not been conducted with gepotidacin.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

No carcinogenicity studies conducted; no reason given in the review

“13.1.4.3. Carcinogenicity No studies were available.”

✓ VerifiedFDA integrated review, p. 136Source ↗

Summary across all 211 small molecules →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Email me this as a cited memo

Same question, other small molecules