FDA Approves Brinsupri (brensocatib) for NCFB Treatment

On August 12, 2025, the U.S. Food and Drug Administration (FDA) approved Brinsupri (brensocatib), a novel, first-in-class dipeptidyl peptidase 1 (DPP1) inhibitor for the treatment of non-cystic fibrosis bronchiectasis (NCFB) in patients aged 12 and older.

This approval marks a significant milestone, providing the first targeted therapy for a chronic respiratory condition with a high unmet medical need. Developed by Insmed Incorporated, brensocatib works by inhibiting the activation of neutrophil serine proteases, key drivers of the inflammatory lung damage characteristic of NCFB.

Approval was based on robust data from the Phase 3 ASPEN and Phase 2 WILLOW trials, which demonstrated that once-daily oral brensocatib (10 mg and 25 mg) significantly reduced the rate of and prolonged the time to pulmonary exacerbations compared to placebo. The safety profile is well-characterized, with key warnings related to dermatologic and periodontal adverse reactions. No REMS is required for this product.

Overview of the Drug

Brinsupri (brensocatib) is a new molecular entity that offers a targeted approach to managing NCFB, a chronic respiratory condition characterized by irreversible bronchial dilation, impaired mucus clearance, and recurrent pulmonary infections that lead to progressive lung function decline.

NCFB represents a significant disease burden with a complex pathophysiology centered on a vicious cycle of infection and inflammation. Neutrophils, a type of white blood cell, play a central role in this inflammatory cascade. Brinsupri is designed to interrupt this cycle at a key point: neutrophil maturation.

The approval of 10 mg and 25 mg once-daily oral tablets provides flexible dosing options for clinicians and patients. Its approval as a first-in-class agent signifies a shift from symptom management and antibiotic cycling to a disease-modifying strategy that targets the underlying inflammatory drivers of NCFB.

The drug’s development program successfully established a favorable benefit-risk profile, leading to its approval without a required Risk Evaluation and Mitigation Strategy (REMS).

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Indications & Patient Selection

Brinsupri is specifically indicated for the treatment of non-cystic fibrosis bronchiectasis (NCFB) in adult and pediatric patients 12 years of age and older.

Patient selection for Brinsupri should be based on a confirmed diagnosis of NCFB. The pivotal clinical trials enrolled a broad population representative of patients seen in clinical practice. Key inclusion criteria in the Phase 3 ASPEN trial included a clinical history of NCFB confirmed by chest computed tomography and a history of recurrent pulmonary exacerbations (at least two in the prior 12 months for adults and at least one for adolescents).

Patients with a variety of NCFB etiologies were included, enhancing the generalizability of the findings. Clinicians should consider Brinsupri for patients aged 12 and over who experience recurrent exacerbations despite standard management, as this population aligns with those who demonstrated the most significant benefit in clinical studies.

Dosing & Administration

The recommended dosage of Brinsupri is either 10 mg or 25 mg taken orally once daily. The tablets can be administered with or without food. If a patient misses a dose, they should take the next scheduled dose at its regular time the following day and should not double the dose to make up for the missed one.

Renal and Hepatic Adjustments

No dosage adjustments are necessary for patients with impaired renal or hepatic function. Clinical pharmacology studies demonstrated no clinically significant differences in the pharmacokinetics of brensocatib in patients with 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).

Mechanism of Action

Brensocatib is a competitive and reversible small molecule inhibitor of dipeptidyl peptidase 1 (DPP1), also known as Cathepsin C. DPP1 is a lysosomal cysteine protease predominantly expressed in hematopoietic cells, where it plays a critical upstream role in the maturation of neutrophils.

Within the bone marrow, DPP1 functions to cleave and activate a cascade of pro-inflammatory neutrophil serine proteases (NSPs), including neutrophil elastase (NE), cathepsin G (CatG), and proteinase 3 (PR3). In NCFB, the airways are chronically infiltrated by activated neutrophils that release these NSPs. This excessive protease activity leads to direct lung tissue destruction, mucus hypersecretion, impaired ciliary function, and perpetuation of the inflammatory cycle.

By inhibiting DPP1, brensocatib prevents the activation of these NSPs in maturing neutrophils. Consequently, circulating neutrophils have a substantially reduced load of active proteases to release upon activation in the airways. This targeted intervention is designed to reduce the intensity of the neutrophil-mediated inflammatory response, thereby mitigating airway damage and reducing the frequency of pulmonary exacerbations.

Clinical Evidence

The efficacy of Brinsupri was established in two adequate and well-controlled multinational trials, the Phase 3 ASPEN study and the Phase 2 WILLOW study.

ASPEN (NCT04594369): A Phase 3 Confirmatory Trial

The ASPEN trial was a 52-week, randomized, double-blind, placebo-controlled study that enrolled 1,721 patients aged 12 years and older with NCFB and a history of frequent exacerbations. Patients were randomized (1:1:1) to receive brensocatib 10 mg, brensocatib 25 mg, or placebo once daily.

The primary endpoint was the annualized rate of pulmonary exacerbations (PEx). Both doses of brensocatib met the primary endpoint with high statistical significance.

• The 10 mg dose resulted in an annualized PEx rate of 1.02, representing a 21% relative reduction compared to the placebo rate of 1.29 (Rate Ratio: 0.79; 95% CI: 0.68, 0.92).
• The 25 mg dose resulted in an annualized PEx rate of 1.04, representing a 19% relative reduction compared to placebo (Rate Ratio: 0.81; 95% CI: 0.69, 0.94).

Both doses also demonstrated statistically significant improvements in key secondary endpoints, including prolonging the time to first exacerbation and increasing the proportion of patients who remained exacerbation-free throughout the 52-week study period. Notably, 48.5% of patients in both brensocatib arms were PEx-free at Week 52, compared to 40.3% in the placebo arm.

WILLOW (NCT03218917): A Phase 2 Proof-of-Concept Trial

The WILLOW trial provided supportive evidence in a 24-week, randomized, double-blind, placebo-controlled study of 256 adult patients with NCFB and a history of at least two exacerbations in the prior year.

The primary endpoint was the

time to first PEx. Both doses of brensocatib significantly extended the time to first exacerbation compared to placebo.

• The 10 mg dose demonstrated a 42% reduction in the risk of a first exacerbation (Hazard Ratio: 0.58; 95% CI: 0.35, 0.95).
• The 25 mg dose demonstrated a 38% reduction in the risk of a first exacerbation (Hazard Ratio: 0.62; 95% CI: 0.38, 0.99).

Trial Comparison	ASPEN (NCT04594369)	WILLOW (NCT03218917)
Phase	3	2
Duration	52 Weeks	24 Weeks
Population	Adults & Adolescents (≥12 yrs) with NCFB	Adults (≥18 yrs) with NCFB
N	1721	256
Primary Endpoint	Annualized Rate of PEx	Time to First PEx
10 mg vs. Placebo	Rate Ratio: 0.79 (95% CI: 0.68, 0.92)	Hazard Ratio: 0.58 (95% CI: 0.35, 0.95)
25 mg vs. Placebo	Rate Ratio: 0.81 (95% CI: 0.69, 0.94)	Hazard Ratio: 0.62 (95% CI: 0.38, 0.99)

Safety Profile

The safety of Brinsupri has been established through a comprehensive clinical program. In the pivotal ASPEN trial, the overall incidence of adverse events was comparable between the brensocatib and placebo arms. There were no major imbalances in deaths, serious adverse events (SAEs), or discontinuations due to adverse events. A REMS was not deemed necessary.

Common Adverse Events

The most common adverse reactions reported in the ASPEN trial (≥2% incidence and greater than placebo in at least one arm) were upper respiratory tract infection, headache, rash, dry skin, hyperkeratosis, and hypertension. The incidence of skin-related events (rash, dry skin, hyperkeratosis) and headache showed a dose-dependent trend.

Serious Adverse Events

No specific serious adverse events were identified as being causally linked to brensocatib. The overall rate of SAEs was slightly lower in the brensocatib arms compared to placebo in the ASPEN trial (17.4% for 10 mg, 16.9% for 25 mg, vs. 19.2% for placebo).

Boxed Warning

Brinsupri does not have a Boxed Warning.

Warnings and Precautions

• Dermatologic Adverse Reactions: An increased incidence of rash, dry skin, and hyperkeratosis was noted. Patients should be monitored for new or worsening skin conditions, with referral to a dermatologist as clinically appropriate.
• Gingival and Periodontal Adverse Reactions: An increased incidence of dental issues was observed. Patients are advised to maintain routine dental hygiene and undergo regular dental checkups.
• Live Attenuated Vaccines: The safety and effectiveness of live attenuated vaccines administered during Brinsupri treatment are unknown. Therefore, their use should be avoided.

Special Populations

• Pregnancy: There are no available data on the use of Brinsupri in pregnant women to assess for drug-associated risks. In animal studies, malformations were observed in rats at exposures 128 times the maximum recommended human dose (MRHD), but no adverse effects were seen in rabbits at exposures up to 20 times the MRHD.
• Lactation: It is not known if brensocatib or its metabolites are present in human milk, or what effects they may have on the breastfed infant or milk production.
• Pediatric Use: The safety and effectiveness of Brinsupri have been established in patients aged 12 years and older, supported by data from 41 adolescents in the ASPEN trial. Common adverse reactions were consistent with the adult population. Studies in children younger than 12 have not been conducted.
• Geriatric Use: In clinical trials, 51% of Brinsupri-treated patients were 65 years or older. No overall differences in safety or effectiveness were observed between geriatric and younger adult patients.

Drug–Drug Interactions & Contraindications

Contraindications

There are no contraindications for Brinsupri.

Drug–Drug Interactions

Brensocatib is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).

• Strong CYP3A4/P-gp Inhibitors (e.g., clarithromycin): Concomitant use significantly increases brensocatib exposure (AUC increased by 55%).
• Moderate CYP3A4/P-gp Inhibitors (e.g., verapamil): Concomitant use increases brensocatib exposure (AUC increased by 32%).
• Strong CYP3A4 Inducers (e.g., rifampin): Concomitant use decreases brensocatib exposure (AUC decreased by 33%).

Despite these pharmacokinetic interactions, no dose adjustments are recommended. Brensocatib does not have a clinically significant effect on CYP3A4 substrates like midazolam.

Pharmacokinetics/Pharmacodynamics

• Absorption: Brinsupri is rapidly absorbed, with a median time to maximum concentration (T_max) of 1.0 to 1.4 hours. Administration with a high-fat meal does not have a clinically relevant effect on its pharmacokinetics.
• Distribution: Brensocatib has an estimated volume of distribution of 126 to 138 L and is 87.2% bound to human plasma proteins.
• Metabolism: It is primarily metabolized by CYP3A, with minor contributions from CYP2C8 and CYP2D6.
• Elimination: The elimination half-life ranges from 25 to 39 hours. Excretion is primarily renal (54.2% of dose) with a smaller portion via feces (28.3%).
• Pharmacodynamics: Brensocatib treatment leads to a dose-dependent reduction in NSP activity in patients with NCFB.

Regulatory Path & Milestones

Brensocatib’s development was expedited due to the significant unmet need in NCFB. The FDA granted the application Breakthrough Therapy Designation on June 5, 2020, recognizing its potential to provide a substantial improvement over available therapies. The NDA, submitted on December 12, 2024, was also granted a Priority Review, leading to an approval decision on August 12, 2025. The FDA did not convene an Advisory Committee meeting, concluding that the data demonstrated a favorable benefit-risk profile without the need for public discussion.

Global Context

• European Medicines Agency (EMA): Not Still approved
• Central Drugs Standard Control Organisation (CDSCO), India: Not Still approved

Practical Considerations

For clinicians managing patients with NCFB, the approval of Brinsupri offers the first targeted, non-antibiotic oral therapy to reduce the frequency of exacerbations. The choice between the 10 mg and 25 mg doses allows for individualized treatment. While both doses showed comparable efficacy in reducing exacerbations, the 25 mg dose demonstrated a statistically significant, albeit small, improvement in FEV1.

The dose-dependent increase in certain adverse events, particularly skin-related issues, may guide the decision to initiate at or use the 10 mg dose in some patients. Proactive counseling on the importance of routine dental hygiene and monitoring for skin changes is essential for patient management.

Limitations & Evidence Gaps

While the clinical program for Brinsupri was robust, some evidence gaps remain. The long-term safety profile beyond 52 weeks has yet to be fully characterized. The clinical significance of the small improvement in FEV1 observed with the 25 mg dose requires further real-world evaluation. Efficacy and safety data in children under 12 years of age are not yet available; a postmarketing requirement is in place to study the 6-to-11-year-old population. The impact of treatment on rarer etiologies of NCFB is also an area for future investigation.

FAQs

Summary

Brinsupri (brensocatib) is a new, once-daily prescription tablet approved by the FDA on August 12, 2025, to help manage non-cystic fibrosis bronchiectasis (NCFB) in adults and children 12 and older. NCFB is a long-term lung condition where the airways become damaged and widened, leading to a build-up of mucus and frequent, serious lung infections. Before Brinsupri, there were no FDA-approved medications specifically for this condition.

Brinsupri works differently from antibiotics by targeting the body’s own inflammatory cells that cause lung damage. In clinical trials, it was shown to significantly reduce the number of lung infections and help patients go longer without an infection compared to a placebo. The most common side effects include upper respiratory infections, headache, and skin issues like rash or dry skin. Because it can also affect dental health, regular checkups with a dentist are important. This new medicine represents a major step forward, offering a targeted way to control the inflammation that drives NCFB. As with any medication, patients should discuss the potential benefits and risks with their healthcare provider.

References

1. U.S. Food and Drug Administration. Brinsupri (brensocatib) tablets, for oral use. Prescribing Information. NDA 217673. Insmed Incorporated. Revised August 2025.[https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217673s000lbl.pdf]
2. U.S. Food and Drug Administration. NDA 217673 Approval Letter. August 12, 2025.[https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/217673Orig1s000ltr.pdf]
3. U.S. Food and Drug Administration. Integrated Review for NDA 217673 Brinsupri (brensocatib). August 7, 2025.[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/217673Orig1s000IntegratedR.pdf]
4. U.S. Food and Drug Administration. Division of Risk Management (DRM) Review for NDA 217673. August 8, 2025.[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/217673Orig1s000RiskR.pdf]
5. U.S. Food and Drug Administration. IND 133790 Breakthrough Therapy Designation Determination Review Template. June 2, 2020.