Brensocatib decreases annualized exacerbation rate in bronchiectasis

Key takeaways:

• Brensocatib given as 10 mg or 25 mg performed better than placebo for three outcomes related to pulmonary exacerbations.
• COVID-19 was a common treatment-emergent adverse event in each brensocatib dose.

Among patients with non-cystic fibrosis bronchiectasis, once-daily brensocatib for 52 weeks lowered the annualized pulmonary exacerbation rate and was well tolerated, according to topline results from the ASPEN trial.

“There are currently no licensed treatments for bronchiectasis,” James D. Chalmers, MBChB, PhD, professor and consultant respiratory physician at the University of Dundee School of Medicine in the United Kingdom, told Healio. “If this treatment becomes available, we will finally have a proven treatment that can reduce pulmonary exacerbations, reduce the burden of this condition and potentially also slow down the progression of the disease.

“For clinicians, and for their patients, this is really exciting to have a new effective treatment for this devastating disease,” he added.

In the phase 3, global, randomized, double-blind, placebo-controlled ASPEN trial, the intent-to-treat population included 1,680 adults and 41 adolescents with non-cystic fibrosis bronchiectasis. Chalmers and colleagues determined the impact of once-daily 10 mg brensocatib (Insmed; n = 582) and 25 mg brensocatib (n = 574) vs. placebo (n = 563) on pulmonary exacerbation rate at 52 weeks.

As Healio previously reported, the phase 2, randomized, double-blind, placebo-controlled, parallel-group WILLOW study found that treatment with brensocatib for 24 weeks significantly prolonged time to first pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis compared with placebo.

This small molecule, oral, reversible inhibitor of dipeptidyl-peptidase 1 was also granted breakthrough therapy designation by the FDA back in 2020.

“ASPEN represents a huge effort by the international bronchiectasis community to perform a landmark trial in a ‘neglected disease,’” Chalmers said.

Efficacy

By the 52-week mark, patients receiving 10 mg brensocatib vs. placebo had a 21.1% reduction in the annualized rate of exacerbations (P = .0019). Researchers observed a similar significant decrease in this exacerbation rate by 19.4% when comparing patients receiving 25 mg brensocatib with those receiving placebo (P = .0046).

In addition to lowering the annualized rate of exacerbations, both doses of brensocatib vs. placebo prolonged the time to first pulmonary exacerbation (10 mg, 18.7%; P = .01; 25 mg, 17.5%; P = .0182).

Researchers also found significant heightened odds for remaining exacerbation free over the 1-year study period in the brensocatib groups. Compared with placebo, the odds for this outcome went up by 41.2% (P = .0059) among those receiving 10 mg brensocatib and by 40% (P = .0074) among those receiving 25 mg brensocatib.

When assessing the change in baseline FEV₁ at 52 weeks, researchers noted a significant difference between the 25 mg brensocatib group and the placebo group (38 mL; P = .0054) but no significant difference between the 10 mg group and the placebo group.

“This suggests that brensocatib is slowing the rate of lung function decline over time, suggesting it doesn’t just prevent exacerbations but might be disease modifying,” Chalmers told Healio. “This is really exciting because we have no other treatments that can slow down the progression of the disease.”

Safety

In terms of safety, slightly more patients receiving placebo experienced a treatment-emergent adverse event than patients receiving 10 mg or 25 mg brensocatib (79.6% vs. 77.7% vs. 76.7%).

This pattern was also seen when evaluating severe treatment-emergent adverse events, with a greater proportion of patients in the placebo group vs. the 10 mg and 25 mg brensocatib groups reporting these types of events (16% vs. 12.7% vs. 11.7%).

Further, serious treatment-emergent adverse events occurred more often in the placebo group (19.2%) than in the 10 mg brensocatib group (17.4%) or the 25 mg brensocatib group (16.9%).

The most common treatment-emergent adverse event in the brensocatib groups was COVID-19, which impacted 15.8% of patients receiving 10 mg brensocatib, 20.9% of patients receiving 25 mg brensocatib and 15.8% of patients receiving placebo.

Other adverse events that impacted the brensocatib groups more than the placebo group included nasopharyngitis (10 mg, 7.7% vs. 25 mg, 6.3% vs. placebo, 7.6%), cough (10 mg, 7% vs. 25 mg, 6.1% vs. placebo, 6.4%) and headache (10 mg, 6.7% vs. 25 mg, 8.5% vs. placebo, 6.9%).

Researchers listed four treatment-emergent adverse events as special interest: hyperkeratosis, periodontal/gingival event, severe infection and pneumonia. The event most experienced by patients from all three groups was pneumonia (10 mg, 4%; 25 mg, 4.7%; placebo, 5.9%).

The remaining three adverse events occurred in smaller proportions of patients in the 10 mg brensocatib group (0.7%-1.4%), the 25 mg brensocatib group (1.2%-3%) and the placebo group (0.7%-2.7%).

Lastly, across all three groups, a similar proportion of patients discontinued treatment due to an adverse event (placebo, 4.1%; 10 mg brensocatib, 4.3%; 25 mg brensocatib, 3.8%) and died due to an adverse event (placebo, n = 7; 10 mg brensocatib, n = 3; 25 mg brensocatib, n = 4).

“ASPEN is a landmark study,” Chalmers said. “It is by far the biggest trial ever conducted in bronchiectasis and the first phase 3 trial with this novel mechanism of action.”

Looking ahead, Chalmers told Healio this trial offers insight into what next steps researchers can take in future studies.

“Bronchiectasis is an inflammatory disease, and a strategy based on reducing inflammation with brensocatib can be effective in reducing exacerbations and slow down progression of the disease,” he said. “Prior to ASPEN most studies in bronchiectasis were focused on antibiotics and did not show efficacy. ASPEN potentially opens up a new era in which we try to tackle the inflammation instead of always focusing on infection.”

This trial also highlights how a dipeptidyl peptidase 1 inhibitor can alter disease progression.

“ASPEN shows that with the right mechanism it may be possible to slow down disease progression and so future trials may focus on disease modification using lung function and CT, rather than only focusing on exacerbations, which are really important but are not the only problem that patients face,” Chalmers said.

The press release noted that there are FDA new drug application submission plans set to take place in the last quarter of this year. Additionally, more detailed findings will be presented at a future medical meeting.

“ASPEN shows that large trials in bronchiectasis are feasible and can be highly successful, which will likely stimulate greater therapeutic development in bronchiectasis in the future,” Chalmers said.