Brexafemme
ibrexafungerp
Species
RatDog
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
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“The 13-week studies were conducted with the citrate salt form which is the ibrexafungerp form in the current clinical formulation and these studies included 14-day recovery periods.”
Study lengthopen answer page →
Longest pivotal study
26 (26-week rat)
“Daily administration of oral ibrexafungerp for 26 weeks in rats, at the highest dose of 80 mg/kg/day (approximately 10 times the RHD based on AUC comparison), was associated with marked, but reversible, phospholipidosis and foamy histiocytes in alveolar tissue in the lung and labored breathing, marked irritation and metaplasia in gastric mucosa, and peripheral nerve degeneration accompanied by hind-limb paralysis.”
Pivotal GLP studies
1-month and 13-week oral studies in rats and dogs
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
Route in tox
Oral gavage
“Administration of SCY-078 citrate by once daily oral gavage for 13 weeks was well tolerated in dogs at dose levels of 15, 30, and 60 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus assays
“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”
Carcinogenicity
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Reproductive & developmental
Rabbit EFD: limb, ear and body-wall malformations at about 5x human exposure
“In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with fetal malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately 5 times the human exposure at the RHD.”
Safety pharmacology
hERG IC50 about 1.4-fold the clinical Cmax
“Results from an in vitro hERG assay indicated that the ibrexafungerp IC50 for hERG inhibition was 1.4-fold higher than the plasma Cmax value associated with the recommended clinical dose of 600 mg/day ibrexafungerp in fed patients.”
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 Brexafemme 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: Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month) (FDA multi-discipline review, p. 42)
NOAEL / key findings
Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month)
“Several ibrexafungerp-related toxicities with potential clinical relevance occurred in a dose-dependent manner in the 1-month toxicology study in rats including degeneration of skeletal muscle cells and stomach glandular mucosa and single-cell necrosis of hepatocytes.”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid necrosis in high-dose rats (1-month study)
“Thymus: Very slight lymphoid necrosis in the thymus was observed in 3/10 HD males and moderate lymphoid necrosis was observed in 1/10 HD females.”
Biodistribution & persistence
Extensive tissue distribution (large intestine, pituitary, bone marrow, liver); no radioactivity in brain/CNS
“Extensive distribution to tissues was observed with the highest concentrations in large intestine, pituitary gland, bone marrow, and liver followed by lung and kidney, minimal concentrations in male reproductive organs, and no detectable radioactivity in brain and CNS tissues.”
Modality-specific risk
Embryofetal toxicity (rabbit malformations)
“Ibrexafungerp was associated with serious dose-related fetal malformations in rabbits at exposures 5- to 13-times the expected clinical exposure.”