Description for Brinsupri
BRINSUPRI (brensocatib) is a dipeptidyl peptidase 1 (DPP1) inhibitor.
The chemical name for the active ingredient brensocatib monohydrate is (2S)-N-{(1S)-1- cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide monohydrate with a chemical formula of C23H24N4O4 • H2O which corresponds to a molecular weight of 438.48 g/mol. Its structural formula is:
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Brensocatib monohydrate drug substance is a white to off-white solid powder. It is slightly soluble at pH 1.2, freely soluble at pH 4.5, and very slightly soluble at pH 6.8 of aqueous media. It is also soluble in acetonitrile and sparingly soluble in ethanol.
BRINSUPRI tablets are available for oral administration in strengths of 10 mg and 25 mg brensocatib with the following inactive ingredients: dibasic calcium phosphate dihydrate, glyceryl dibehenate, microcrystalline cellulose, silicon dioxide, and sodium starch glycolate. The film coating contains ferrosoferric oxide/black iron oxide, iron oxide yellow, and iron oxide red (10 mg) or ferrosoferric oxide/black iron oxide (25 mg), macrogol/PEG, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
- Dermatologic Adverse Reactions [see Warnings and Precautions (5.1)]
- Gingival and Periodontal Adverse Reactions [see Warnings and Precautions(5.2)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data below reflect the safety of BRINSUPRI in adult and pediatric patients aged 12 years and older with non-cystic fibrosis bronchiectasis (NCFB). A total of 1721 patients with NCFB were randomized in a double-blind, placebo-controlled clinical trial of 52 weeks duration (ASPEN) [see Clinical Studies (14)]. The safety of BRINSUPRI was based on data from 1719 adult and pediatric patients aged 12 years and older who received at least one dose of BRINSUPRI or placebo. A total of 1156 patients received at least one dose of BRINSUPRI 10 mg or 25 mg orally once daily.
Table 1 shows the adverse reactions occurring at an incidence of >2% and higher in BRINSUPRI-treated patients compared to placebo in the safety population from ASPEN.
Table 1 Adverse Reactions with BRINSUPRI with an Incidence of >2% and More Common than Placebo in ASPEN
| Adverse Reaction | Placebo (N=563) n (%) |
BRINSUPRI 10 mg QD (N=582) n (%) |
BRINSUPRI 25 mg QD (N=574) n (%) |
|
| Upper respiratory tract infection1 | 141 (25) | 157 (27) | 169 (29) | |
| Headache | 39 (7) | 39 (7) | 49 (9) | |
| Rash2 | 22 (4) | 25 (4) | 35 (6) | |
| Dry skin3 | 8 (1) | 17 (3) | 25 (4) | |
| Hyperkeratosis4 | 5 (1) | 8 (1) | 16 (3) | |
| Hypertension | 17 (3) | 28 (5) | 13 (2) | |
|
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Adverse Reactions in WILLOW
A total of 256 adult patients with NCFB were randomized in the 24-week, double-blind, placebo-controlled clinical trial (WILLOW). Of those randomized, 255 adult patients received BRINSUPRI 10 mg, BRINSUPRI 25 mg, or placebo, which consisted of 170 adults treated with at least one dose of BRINSUPRI 10 mg or 25 mg orally once daily. The safety profile for adult patients with NCFB in WILLOW was generally similar to ASPEN, with the exception of a higher incidence of gingival and periodontal adverse reactions. The incidence of gingival and periodontal adverse reactions in WILLOW among patients treated with BRINSUPRI 10 mg and 25 mg were 9.9% and 10.1%, respectively, compared to 2.4% in placebo-treated patients.
Less Common Adverse Reactions
Liver Function Test Elevations
In ASPEN, there was an increase from baseline in average ALT, AST, and alkaline phosphatase levels at all time points from Week 4 through Week 56 in both BRINSUPRI 10 mg and 25 mg arms compared to placebo. The incidence of ALT >3X upper limit of normal (ULN) was 0%, 1.2%, and 0.9%, in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively. The incidence of AST >3X ULN was 0.2%, 0.3%, and 0.5% in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively. The incidence of alkaline phosphatase >1.5X ULN was 2.5%, 4.1%, and 4.0% in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively.
Skin Cancers
In ASPEN, the incidence of skin cancers among patients treated with BRINSUPRI 10 mg and 25 mg was 0.5% and 1.9%, respectively, compared to 1.1% in placebo- treated patients.
Alopecia
In ASPEN, the incidence of alopecia among patients treated with BRINSUPRI 10 mg and 25 mg was 1.5% and 1.6%, respectively, compared to 0.4% in placebo-treated patients.
Drug Interactions for Brinsupri
No information provided
Warnings for Brinsupri
Included as part of the PRECAUTIONS section.
Precautions for Brinsupri
Dermatologic Adverse Reactions
Treatment with BRINSUPRI is associated with an increase in dermatologic adverse reactions, including rash, dry skin, and hyperkeratosis [see Adverse Reactions (6.1)]. Monitor patients for development of new rashes or skin conditions and refer patients to a dermatologist for evaluation of new dermatologic findings.
Gingival and Periodontal Adverse Reactions
Treatment with BRINSUPRI is associated with an increase in gingival and periodontal adverse reactions [see Adverse Reactions (6.1)]. Refer patients to dental care services for regular dental checkups while taking BRINSUPRI. Advise patients to perform routine dental hygiene.
Live Attenuated Vaccines
The concomitant use of BRINSUPRI and live attenuated vaccines has not been evaluated. It is unknown whether administration of live attenuated vaccines during BRINSUPRI treatment will affect the safety or effectiveness of these vaccines. The use of live attenuated vaccines should be avoided in patients receiving BRINSUPRI.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year study in Han Wistar rats and a 6-month study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of brensocatib. No evidence of tumorigenicity was observed in male or female rats at an exposure approximately 56 times the MRHD on an AUC basis. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice at oral doses up to 50 mg/kg/day, the highest dose tested.
Brensocatib was negative for genotoxicity in the following assays: in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, and in vivo micronucleus assay in rats.
Oral administration of brensocatib to male and female rats at up to 50 and 100 mg/kg/day, respectively, had no adverse effects on fertility and reproductive performance indices (150 and 231 times the MRHD on an AUC basis, respectively).
Clinical Pharmacology for Brinsupri
Mechanism of Action
Brensocatib is a competitive, reversible inhibitor of dipeptidyl peptidase 1 (DPP1). DPP1 activates pro-inflammatory neutrophil serine proteases (NSPs) during neutrophil maturation in the bone marrow. Activated NSPs are implicated in the pathogenesis of neutrophil-mediated NCFB inflammation. In cell-based assays, DPP1 inhibition by brensocatib reduces the activity of NSPs including neutrophil elastase, cathepsin G, and proteinase 3.
Pharmacodynamics
Brensocatib prevents the activation of NSPs via DPP1 inhibition resulting in decreases in NSP activity in patients. In exploratory assays, brensocatib was associated with dose- dependent reductions in NSP activity in patients with NCFB.
Cardiac Electrophysiology
At concentrations approximately 2 times the steady state peak concentration of the maximum recommended daily dose of brensocatib in adult and adolescents with NCFB, clinically significant QTc interval prolongation was not observed.
Pharmacokinetics
Following once daily administration of brensocatib 10 mg, the estimated geometric mean (CV%) Cmax is 85.4 ng/mL (33%) and AUCtau is 1360 ng*h/mL (41%). Following once daily administration of brensocatib 25 mg, the estimated geometric mean (CV%) Cmax is 259 ng/mL (31%) and AUCtau is 4060 ng*h/mL (39%).
Brensocatib Cmax and AUCtau increase in a greater than dose proportional manner between doses of 10 mg and 1.6 times the highest recommended dose. Between doses of 10 mg and 1.6 times the highest recommended dose brensocatib once daily, brensocatib geometric mean steady state Cmax increased by 5.1-fold and AUCtau increased by 5.3-fold. In healthy subjects, at steady state, Cmax increased by about 1.5- fold and AUCtau increased by about 2-fold when compared to those observed following a single dose.
No clinically relevant differences in brensocatib pharmacokinetics were observed between healthy subjects and patients with NCFB.
Absorption
The absolute oral bioavailability of brensocatib has not been studied in humans. Based on data from a mass balance study in healthy subjects, the oral absorption of brensocatib in humans is greater than 80%. Following a single dose of 10 mg or 25 mg brensocatib, the median (min, max) time to maximum plasma concentration (Tmax) is 1.0-1.4 hours (0.5, 3.0 hours).
Effect of Food
No clinically relevant differences in brensocatib pharmacokinetics were observed following administration of brensocatib with a high-fat meal (990 calories, 52% fat).
Distribution
Following once daily administration of 10 mg or 25 mg brensocatib in patients with NCFB, the estimated volume of distribution at steady state ranged from 126 to 138 L. The protein binding of brensocatib in human plasma was 87.2%.
Elimination
Following a single oral administration of brensocatib at 10 mg or 25 mg in healthy subjects, the elimination half-life ranged from 25 to 39 hours and the apparent oral clearance ranged from 6.4 to 10.7 L/hour.
Metabolism
Brensocatib is primarily metabolized by CYP3A and to a lesser extent by CYP2C8 and CYP2D6. Brensocatib accounted for 16.2% of the total radioactivity in plasma. One major circulating metabolite, thiocyanate, was identified in plasma and accounted for 51% of the total radioactivity AUC following administration of a radio-labeled brensocatib dose. In patients with NCFB at recommended doses of brensocatib, no clinically meaningful changes of plasma thiocyanate from baseline were observed.
Excretion
Following administration of a single oral dose of radiolabeled brensocatib 1.6 times the highest recommended dose to healthy subjects, 54.2% of dose was recovered in urine (22.8% as unchanged brensocatib) and 28.3% of dose was recovered in feces (2.4% as unchanged brensocatib).
Specific Populations
No clinically significant differences in the pharmacokinetics of brensocatib were observed based on age (12 to 85 years), sex, race (72% White, 6% Black, and 12% Asian), or body weight (32 to 155 kg).
No clinically significant differences in the pharmacokinetics of brensocatib were observed based on mild, moderate, or severe renal impairment (eGFR 15-89 mL/min/1.73 m2); or mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Strong CYP3A4 and P-gp Inhibitors: Brensocatib Cmax increased by 68% and AUC increased by 55% following concomitant administration with clarithromycin (a strong CYP3A4 and P-gp inhibitor) 500 mg twice daily for 6 days.
Moderate CYP3A4 and P-gp Inhibitors: Brensocatib Cmax increased by 53% and AUC increased by 32% following concomitant administration with verapamil (a moderate CYP3A4 and P-gp inhibitor) 240 mg once daily for 5 days.
Strong CYP3A4 Inducers: Brensocatib Cmax decreased by 15% and AUC decreased by 33% following concomitant administration with rifampin (a strong CYP3A4 inducer) 600 mg once daily for 9 days.
Acid-Reducing Agents: Brensocatib Cmax and AUC were unchanged following concomitant administration with esomeprazole (a proton-pump inhibitor) 40 mg once daily for 4 days.
CYP3A4 Substrates: No clinically significant differences in the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) are predicted when used concomitantly with brensocatib.
In Vitro Studies
CYP450 Enzymes: Brensocatib is a substrate of CYP3A. Brensocatib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Brensocatib is weak CYP3A inducer, but not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Transporter Systems: Brensocatib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2. Brensocatib is an inhibitor of BCRP, OATP1B, MATE1, and MATE2-K, but is not an inhibitor of P-gp, OAT1, OCT2, OAT3, or OATP1B3.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Dermatologic Adverse Reactions
Inform patients that BRINSUPRI is associated with a risk of adverse skin reactions including rash, dry skin, and hyperkeratosis. Advise patients to monitor their skin and report any new rash or skin condition [see Warnings and Precautions (5.1)].
Gingival and Periodontal Adverse Reactions
Inform patients that BRINSUPRI is associated with a risk of gingival and periodontal adverse reactions. Advise patients to have regular dental checkups while taking
BRINSUPRI. Advise patients to perform routine dental hygiene [see Warnings andPrecautions (5.2)].
Live Attenuated Vaccines
Instruct patients to inform the healthcare provider that they are taking BRINSUPRI prior to a potential vaccination [see Warnings and Precautions (5.3)].
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