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.”
Species: general tox
Rat and dog
“repeat-dose toxicology studies conducted in the rat and dog for durations up to 26 weeks and 39 weeks, respectively”
Species: DART
Rat and rabbit (full reproductive toxicology battery)
“a full battery of reproductive toxicology studies in rat and rabbit”
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (6-month)
“2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies”
Surrogate used in
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.
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”
Genotox: Ames
Negative (Ames)
“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.”
Genotox: in vitro mammalian
Mouse lymphoma TK locus assay: negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
2-year rat; 6-month Tg.rasH2 mouse
“2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies”
Carcinogenicity timing
104-week rat and 6-month Tg rasH2 mouse completed before the marketing application
“The carcinogenic potential of brensocatib was assessed in a 6-month Tg Ras mouse study and in a 104- week carcinogenicity study in rats.”
hERG / QT
hERG IC50 13.9 uM; 176-fold margin to free Cmax at MRHD (25 mg QD); low arrhythmogenic risk
“Brensocatib blocked the hERG-encoded potassium channel with an IC50 of 13.9 μM. The exposure margin to the free exposure (Cmax) at steady state of 0.079 µM (total Cmax = 0.616 µM or 259 ng/mL) in humans at MRHD (25 mg QD) is 176-fold, indicating a low arrhythmogenic risk.”
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).”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Dermatologic Adverse Reactions
- Gingival and Periodontal Adverse Reactions
- Live Attenuated Vaccines
Skin reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month dog (oral) with 26-week recovery
“a second chronic toxicity study (with 9 months of administration) was conducted in dogs with a lower maximum dose of 8 mg/kg/day and a recovery period of 26 weeks (similar duration to the previous study).”
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”
DART package
Species: DART
Rat and rabbit (full reproductive toxicology battery)
“a full battery of reproductive toxicology studies in rat and rabbit”
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%).”
PPND / ePPND: when
PPND in rat (oral) completed before the marketing application
“The potential effect of brensocatib on pre- and postnatal development was investigated in rats after once daily oral dosing from GD6 to LD21 at dose levels of 0, 3, 9 and 20 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (6-month)
“2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies”
Carcinogenicity model
2-year rat; 6-month Tg.rasH2 mouse
“2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies”
Carcinogenicity timing
104-week rat and 6-month Tg rasH2 mouse completed before the marketing application
“The carcinogenic potential of brensocatib was assessed in a 6-month Tg Ras mouse study and in a 104- week carcinogenicity study in rats.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL margins vs human AUC: 26-week dog ~1.4x, 39-week dog ~5.4x, 26-week rat ~20.6x
“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”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
LPS-induced acute lung injury model (no established NCFB model)
“There are no established models for NCFB. Therefore, the Applicant has evaluated the activity of brensocatib in a lipopolysaccharide (LPS)-induced acute lung injury model.”
Why that model
No in vivo animal model of bronchiectasis available
“There is no in vivo animal model of bronchiectasis that provides direct evidence of the non-clinical efficacy of brensocatib.”
Reviewer's view of the efficacy data
FDA: in vitro and in vivo pharmacology sufficient to characterize activity and support clinical trials in NCFB
“The totality of in vitro and in vivo pharmacology data submitted was considered sufficient to characterize the pharmacologic activity of brensocatib and supported the initiation of human clinical trials for the indication of NCFB.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted
No juvenile animal studies; adolescent rat and dog repeat-dose studies used to support patients aged 12 years and older
Why: Animals of both species entered puberty at the start of the studies (ICH S11) · Within the guideline
“Studies in juvenile animals were not conducted.”
“These studies are considered appropriate to support dosing of brensocatib in patients ≥12 years of age as the animals of both species entered puberty at the start of the studies (ICH, S11).”
Impurity or metaboliteCriticised but acceptedBeyond the letter
Nitrosamine impurity follow-up mammalian mutation assay run without hamster S9 and without nitrosamine positive controls
Why: Weight of evidence indicates low mutagenic potential, supported by NSOEG · Weight of evidence
“Unfortunately, it was not performed with hamster S9 mix, at least at low concentrations as it is known to be cytotoxic for many cell cultures. In addition, no nitrosamine positive controls were included in the study.”
“Overall, the weight of evidence indicates a low mutagenic potential of the nitroso impurity and is also supported by NSOEG.”
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