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The FDA has approved Insmed’s brensocatib (Brinsupri)— an oral small-molecule inhibitor of dipeptidyl peptidase 1 (DPP1) — for non-cystic fibrosis bronchiectasis. It is the first drug specifically approved to treat this inflammatory lung disease, which affects an estimated 350,000–500,000 people in the USA.
“The unmet need is massive,” says James Chalmers, a respiratory clinician scientist at the University of Dundee who led the clinical trials of brensocatib.
Insmed’s first-in-class brensocatib could command annual sales of over US$4 billion by 2031, show consensus sales estimates on the Cortellis database. Insmed bought brensocatib from AstraZeneca in 2016 for $160 million.
Bronchiectasis is a chronic, progressive immune-mediated disease that causes excessive mucus production, persistent cough and widening of the airways — impairing lung function. Recurrent exacerbations lead to hospitalization in many patients. Until now, treatment involved physical therapy to promote mucus clearance and antibiotics to tackle associated respiratory infection.
Brensocatib is the first drug to target neutrophils, innate immune cells that home to sites of infection where they engulf pathogens, produce cytokines to recruit other immune cells and release antimicrobial peptides called neutrophil serine proteases (NSPs). Over-activation of neutrophils and excessive NSP production drives bronchiectasis as well as other inflammatory diseases.
The DPP1 protease activates NSPs during neutrophil maturation in the bone marrow. By inhibiting DPP1, brensocatib disarms NSPs while sparing other effector functions of neutrophils that are needed to fight infections.
“Brensocatib now gives you the opportunity to address the underlying disease,” says Martina Flammer, Chief Medical Officer at Insmed. “It is a game-changer.”
In a pivotal trial in 1,721 patients who had experienced at least two exacerbations in the past year, daily brensocatib (10 mg or 25 mg) for 1 year met the primary end point, cutting the annualized rate of exacerbations by 20% versus placebo. In the high-dose group, the rate of decline in lung function was slowed to a level in line with normal ageing. Longer studies are needed to test whether the benefit to lung function persists. The drug was generally safe and well-tolerated, with no effect on the rate of infection.
Over 20 years ago, researchers showed that DPP1-knockout mice were protected against inflammatory arthritis. But a rare genetic condition in humans who lack DPP1 dampened industry interest in the target, as these individuals have substantial abnormalities of the skin and teeth. GSK’s irreversible DPP1 inhibitor GSK2793660 also caused skin abnormalities in a phase II bronchiectasis trial and was discontinued.
Brensocatib is a reversible covalent inhibitor that seems to have hit a sweet spot in DPP1 inhibition. Brensocatib was associated with hyperkeratosis, a thickening of the skin’s outer layer, in some patients in its phase III trial, but this was mostly mild and only led to treatment discontinuation in one patient.
A handful of other DPP1 inhibitors are in development, including two candidates in phase III trials for bronchiectasis. Drug developers are also looking at other inflammatory indications with strong neutrophilic components for these agents (Table 1).
“[Brensocatib is] opening up this pathway for potentially other diseases,” says Kevin Mange, Chief Development Officer at Insmed. “I think you’ll see more coming.”
AstraZeneca retains the rights to brensocatib for asthma and chronic obstructive pulmonary disease (COPD). The company was testing brensocatib in COPD, but removed the drug from its pipeline in 2023. They declined to comment on development plans.