Brenzavvy
bexagliflozin
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 monkey
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
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
“Rats were administered bexagliflozin by oral gavage at doses of 1, 3, 10, or 30 mg/kg/day for 26 weeks”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Monkeys were administered bexagliflozin orally at doses of 2, 6, 20, or 60 mg/kg/day for 39 weeks.”
Pivotal GLP studies
General toxicology studies up to 6 months in rats and 9 months in monkeys
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
Route in tox
Oral (gavage in rats, nasogastric intubation in monkeys)
“39-Week Nasogastric Intubation Toxicity and Toxicokinetics Study With Bexagliflozin in Cynomolgus Monkeys With a 4-Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration, in vivo rat micronucleus and rat unscheduled DNA synthesis assays
“Bexagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro CHO cell assay, an in vivo micronucleus assay in rats, and an in vivo unscheduled hepatic DNA synthesis study in rats.”
Carcinogenicity
2-year SD rat and CD-1 mouse: no neoplastic findings (about 54x and 135x clinical AUC)
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice. There were no neoplastic findings in mice and rats up to the highest doses tested (150 mg/kg/day for mice and 30 mg/kg/day for rats, representing approximately 135 and 54 times the clinical dose of 20 mg based on AUC, respectively).”
Reproductive & developmental
No adverse effects on rat fertility, rat or rabbit embryofetal development, or rat pre/postnatal development
“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”
Safety pharmacology
No hERG effect up to 25 uM (99-fold MRHD Cmax)
“Bexagliflozin did not affect hERG channel-mediated potassium current in HEK293 cells up to the maximum tested concentration of 25 mcM (17,380 ng/mL, 99-fold MRHD based on clinical Cmax of 176 ng/ml)”
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 Brenzavvy 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: NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC) (FDA integrated review, p. 87)
NOAEL / key findings
NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC)
“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Highest rat tissue levels in kidney, liver, adrenal, pancreas, harderian and preputial glands
“In a distribution study in rats, the kidney medulla and cortex, liver, adrenal cortex and medulla, pancreas, harderian gland, and preputial gland showed the highest bexagliflozin concentration between 4 to 12 hours postdose.”
Modality-specific risk
Juvenile renal findings; not recommended in second and third trimesters of pregnancy
“Based on the juvenile animal data, bexagliflozin is not recommended for use during the second and third trimester of pregnancy.”