Effective Date

Date of Origin 

10-01-2025            

10-01-2025

(brensocatib)

Tablet

The FDA has accepted a new drug application (NDA) and granted priority review to brensocatib (INS1007; Insmed Inc) for treatment of non-cystic fibrosis bronchiectasis. It has a Prescription Drug User Fee Act target date of August 12, 2025, and if approved, it will be the first and only FDA-approved treatment for bronchiectasis and the first within a new class of medicines, dipeptidyl peptidase 1 (DPP1) inhibitors, which are meant to treat neutrophil-mediated diseases.

Note: A Study of the Efficacy and Safety of Brensocatib in Participants With Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP) (NCT06013241) is a recruiting/ongoing phase 2b trial. 

Bronchiectasis

Bronchiectasis is an acquired disorder of the major bronchi and bronchioles that is characterized by permanent abnormal dilatation and destruction of bronchial walls. The induction of bronchiectasis requires an infectious insult plus impairment of drainage, airway obstruction, and/or a defect in host defense. There are numerous etiologies that can induce or contribute to the pathophysiologic processes that result in bronchiectasis. They include airway obstruction (e.g., foreign body aspiration), defective host defenses, cystic fibrosis (CF), rheumatic and systemic diseases, dyskinetic cilia, pulmonary infections, and allergic bronchopulmonary aspergillosis (ABPA). The classic clinical manifestations of bronchiectasis are cough on most days of the week, daily production of mucopurulent and tenacious sputum for months to years, and a history of exacerbations. Less specific complaints include dyspnea, hemoptysis, wheezing, and pleuritic chest pain. The diagnosis of bronchiectasis is established based on a combination of typical clinical features (e.g., cough, chronic sputum production, recurrent respiratory infections), and confirmed by characteristic features of bronchial airway dilatation on computed tomography (CT).(2,3)

Management of bronchiectasis with antibiotics is directed at treatment of acute exacerbations as well as prevention of future events. Frequent exacerbations are predictive of future exacerbations that are associated with reductions in quality of life, increases in hospitalization and greater mortality. Acute exacerbations present as an increase in sputum volume or change in color coupled with fatigue, increased dyspnea, pleuritic chest pain, and hemoptysis. In the patient with an exacerbation, antibacterial therapy can be guided by prior sputum bacterial cultures, success or failure with previous regimens, and allergic reactivity to antibiotics.(2,3,4) Underlying causes of bronchiectasis (e.g., CF, primary immunodeficiencies, ABPA, non-tuberculous mycobacteria [NTM], tuberculosis) have distinct pathophysiology, and their own disease-specific treatment pathways.(1,4)

Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Excess activation of neutrophil serine proteases (NSPs) is thought to contribute to perpetuation of inflammation and lung destruction in bronchiectasis, raising the possibility that an inhibitor of NSP activation (brensocatib) might reduce the rate of exacerbations.(1,5,6)

Efficacy

In a phase 2 trial (WILLOW; NCT03218917) 256 participants with non-cystic fibrosis bronchiectasis (NCFBE), who had at least two exacerbations in the prior year, were treated with brensocatib 10 mg daily, brensocatib 25 mg daily, or placebo for 24 weeks. Over the course of the trial, 42 exacerbations occurred in the 25 mg brensocatib group, 34 in the 10 mg brensocatib group, and 54 in the placebo group. The time to first exacerbation was prolonged with brensocatib compared with placebo (adjusted hazard ratio approximately 0.6 in both groups, 95% CI 0.35-0.99).(5)

The ASPEN trial was a randomized, double-blind, placebo-controlled study conducted to assess the efficacy, safety, and tolerability of brensocatib compared with placebo in patients with NCFBE. Patients were enrolled if they had bronchiectasis symptoms (e.g., cough, chronic sputum production, and/or recurrent respiratory infections), a radiologically confirmed diagnosis, and two or more exacerbations (defined by need for antibiotic prescription) in the 12 months prior to enrollment. Exclusions include patients with bronchiectasis due to cystic fibrosis, known or suspected immunodeficiency disorders, known human immunodeficiency virus (HIV) infection, or currently being treated for nontuberculous mycobacteria (NTM) lung infection, allergic bronchopulmonary aspergillosis (ABPA), or tuberculosis (TB).(6)

A total of 1682 patients were enrolled (median age: 61.3 years; 64.7% were female) from December 2020 to March 2023 and randomly assigned to receive either brensocatib (10 mg or 25 mg administered orally) or a matching placebo for 52 weeks. The findings demonstrated that both doses of brensocatib met their primary end point, achieving both statistical and clinical significance for the reduction in the annualized rate of pulmonary exacerbations compared with placebo. Additionally, both doses met multiple prespecified exacerbation-related secondary end points, including significantly prolonging the time to first exacerbation and significantly increasing the odds of remaining exacerbation-free during the 52-week treatment period. Further, patients who were treated with 25 mg of brensocatib also demonstrated a significantly lower lung function decline at the 52-week point.(7)

1

Choi H, McShane PJ, Aliberti S, Chalmers JD. Bronchiectasis management in adults: State of the art and future directions. Eur Respir J. 2024 Jun;63(6):2400518. doi: 10.1183/13993003.00518-2024

2

McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2013;188(6):647-656. doi: 10.1164/rccm.201303-0411CI

3

Lee E, Kim K, Jeon YH, et al. Evidence-based management guidelines for non-cystic fibrosis bronchiectasis in children and adolescents. Clin Exp Pediatr. 2024;67(9):418-426.

4

European Respiratory Society (ERS) guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50(3):1700629. doi: 10.1183/13993003.00629-2017

5

Cipolla D, Zhang J, Korkmaz B, et al. Dipeptidyl peptidase-1 inhibition with brensocatib reduces activity of all major neutrophil serine proteases in patients with bronchiectasis: Results from the WILLOW trial. Respir Res. 2023;24:133. doi: 10.1186/s12931-023-02444-z

6

Chalmers JD, Burgel PR, Daley CL, et al. Brensocatib in non-cystic fibrosis bronchiectasis: ASPEN protocol and baseline characteristics. ERJ Open Res. 2024;10(4):00151-2024. doi: 10.1183/23120541.00151-2024

7

Aksamit TR, Chalmers JD, Burgel PR, et al. Lung function in patients with non-cystic fibrosis bronchiectasis by prespecified subgroups in the phase 3, randomized, double-blind, placebo-controlled ASPEN trial. Chest. 2024 Oct;166(4):A6557-A6559.

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of bronchiectasis and ALL of the following:
      1. The patient has a clinical history consistent with bronchiectasis (e.g., cough, chronic sputum production, recurrent respiratory infections) AND
      2. The patient has had computed tomography (CT) to confirm the diagnosis of bronchiectasis AND
      3. The patient does NOT have cystic fibrosis, primary or secondary immunodeficiency, non-tuberculous mycobacterial (NTM) disease, allergic bronchopulmonary aspergillosis (ABPA), or tuberculosis AND
      4. The patient has had at least two pulmonary exacerbations that required an antibiotic prescription within the past 12 months OR
   2. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient's age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient's age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., pulmonologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., pulmonologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Universal QL

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: 

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication 

Length of Approval: up to 12 months