Brinsupri
brensocatib
Species
RatDog
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 dog
“repeat-dose toxicology studies conducted in the rat and dog for durations up to 26 weeks and 39 weeks, respectively”
Why that species
Pharmacological relevance: brensocatib inhibits DPP1 in mice, rats and dogs as well as humans
“brensocatib is an effective reversible inhibitor of recombinant dipeptidyl peptidase 1 (DPP1) in humans, mice, rats, and dogs, and confirmed the subsequent inhibition of NSP activities (NE, PR3, CatG) in human samples obtained from subjects treated with clinically relevant doses. The in-vitro data also support the selected test species for safety studies with regard to pharmacologically relevance”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 39-week GLP study in dogs, animals were administered 0 (vehicle), 1, 2, 4 or 8 mg/kg/day brensocatib orally for 39 weeks with a 26-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In the 39-week GLP study in dogs, animals were administered 0 (vehicle), 1, 2, 4 or 8 mg/kg/day brensocatib orally for 39 weeks with a 26-week recovery period.”
Pivotal GLP studies
26-week rat, 26-week dog and 39-week dog oral studies
“Table 47. Summary of Brensocatib Exposures in Repeat-Dose Toxicity Studies Study NOAEL (mg/kg/day) AUC (µmol.h/L) Systemic Exposure Margina 26-week rat study 9 196 20.6 26-week dog study 2 13.3 1.4 39-week dog study 8 51.4 5.4”
Route in tox
Oral
“Repeat-dose toxicity studies with oral administration of brensocatib were conducted for up to 6 months in rats and 9 months in dogs in compliance with GLP and ICH M3(R2) requirements.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro mouse lymphoma TK and in vivo rat micronucleus assays
“Brensocatib was found to be negative for genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, an in vitro mouse lymphoma cell thymidine kinase locus assay, and in vivo micronucleus assay in rats.”
Carcinogenicity
104-week rat and 6-month Tg rasH2 mouse: no neoplastic findings (>50x and >60x MRHD unbound AUC)
“No neoplastic findings were observed in a 6-month Tg Ras mouse study and a 104-week carcinogenicity study in rats up to the highest doses tested yielding AUC-based (unbound brensocatib fraction) safety margins of > 60-fold (mice) and > 50-fold (rat) to the MRHD.”
Reproductive & developmental
Rat EFD: bent scapula malformation at 100 mg/kg/day (3.7% of fetuses)
“Drug-related adverse skeletal malformation of bent scapula was observed in fetuses from pregnant dams administered 100 mg/kg/day brensocatib (4 of 110 fetuses, 3.7%).”
Safety pharmacology
No CNS or respiratory effects in rats at oral doses up to 200 mg/kg
“Safety pharmacology studies indicated that brensocatib did not affect the central nervous system or respiratory system in Han Wistar rats at oral doses up to 200 mg/kg”
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 Brinsupri 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 dog: adverse findings at 8 and 50 mg/kg/day in testis/epididymis, lungs, lymphoid tissues, spleen, kidney and teeth (FDA integrated review, p. 134)
NOAEL / key findings
26-week dog: adverse findings at 8 and 50 mg/kg/day in testis/epididymis, lungs, lymphoid tissues, spleen, kidney and teeth
“drug-related adverse findings were evident in the 8 and 50 mg/kg dosing groups in epididymis and testis (male), lungs, lymphoid tissues, spleen, kidney, and teeth.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; weight-of-evidence evaluation showed no concerning immunotoxic risk
“No dedicated immunotoxicity investigations were conducted and there was no evidence of a concerning immunotoxicological risk based on a comprehensive weight-of-evidence evaluation in”
Biodistribution & persistence
Highest levels in liver, preputial gland and uveal tract, suggesting melanin binding; low CNS penetration
“Highest radioactivity tissue concentrations were in the liver and preputial gland in albino rats and in the uveal tract in the pigmented rats, suggesting melanin binding of brensocatib or its metabolites. There is low CNS penetration.”
Modality-specific risk
Severe periodontal disease in dogs at 50 mg/kg/day (>7x MRHD)
“In the 6-month repeat dose toxicology study in dogs, severe periodontal disease was observed at the highest dose administered of 50 mg/kg (greater than 7 times the MRHD).”