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DPP1 Inhibitor Promising in Non-CF Bronchiectasis

— Also being studied now in COVID patients

Ƶ MedicalToday

Treatment with the investigational anti-inflammatory drug brensocatib (formerly INS1007) significantly delayed the time to exacerbation in patients with the rare lung disease non-cystic fibrosis bronchiectasis, researchers reported.

In phase II findings from the , which enrolled 256 adults with at least two documented bronchiectasis exacerbations over the past year, both doses of the oral drug tested (10 and 25 mg/day) delayed the time to first pulmonary exacerbation over the 24-week treatment period compared with placebo.

The study's lead investigator, James Chalmers, PhD, of the University of Dundee, Scotland, presented the study at an held in advance of the full virtual program scheduled for August 5-10.

The time to first bronchiectasis exacerbation was significantly longer in the brensocatib-treated patients compared with those in the placebo group (10 mg treatment hazard ratio [HR] 0.58, 95% CI 0.35-0.95, P=0.029; 25 mg treatment HR 0.42, 95% CI 0.38-0.99, P=0.046).

During the treatment period, 48.3% of the placebo-treated patients had exacerbations, compared with 31.7% of the brensocatib 10 mg and 33.3% of the 25 mg treated patients.

Both doses of brensocatib were well tolerated overall, and the safety profile of both were comparable with placebo, Chalmers reported.

A dose-dependent decline in sputum neutrophil elastase level was also observed, which supports the drug's mechanism of action of reducing neutrophil serine protease (NSP) activation.

The drug's developer, Insmed, funded the trial, and in late April announced that the investigational agent would also be studied .

That study, the , also led by Chalmers, was designed as a multicenter, double-blind, placebo-controlled trial of brensocatib in addition to standard of care for patients with severe COVID-19. The study was designated an "urgent public health trial" by Britain's National Institute for Health Research.

Chalmers said patient recruitment began early in June, with results expected by the end of 2020.

In his presentation at the ATS virtual session, he characterized the WILLOW study as a "landmark" trial for people with non-cystic fibrosis bronchiectasis, a rare pulmonary disorder characterized by frequent exacerbations requiring antibiotic therapy and/or hospitalizations.

"This is a drug that for the first time appears to be able to directly target neutrophilic inflammation, resulting in clinical benefits," he said. "If these results are confirmed in a phase III trial it would represent a novel, non-antibiotic treatment to prevent exacerbations in bronchiectasis."

Brensocatib is a novel oral selective reversible small-molecule inhibitor of the lysosomal cysteine protease dipeptidyl peptidase I (DPP1) -- an enzyme responsible for activating NSPs, including neutrophil elastase, when they are being formed in the bone marrow.

The facilitator for Chalmers's presentation, Jennifer Taylor-Cousar, MD, director of the Cystic Fibrosis Therapeutics Development Center Adult Program at National Jewish Health in Denver, also expressed excitement about the experimental drug. "For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting," she said.

Chalmers explained that bronchiectasis patients generally suffer persistent symptoms and frequent exacerbations, with no approved therapies available.

"There is an urgent need for approved, effective therapies that can break the vicious cycle of inflammation, lung damage, and infection for these patients," he said.

Earlier research by his group showed exacerbation risk and even lung function decline in patients with bronchiectasis to be . Elevated NSPs, including neutrophil elastase, are increased in sputum of patients with bronchiectasis, and elevated NSPs are linked to exacerbations and poor quality of life in patients with the disease.

"This [research] provided some of the rationale for believing that blocking inflammation -- particularly targeting neutrophil serine proteases -- may be associated with clinical benefits in people with bronchiectasis," he said.

Disclosures

This research was funded by Insmed, and Chalmers reported receiving fees related to consultant work and grant funding from the company.

Primary Source

American Thoracic Society

Chalmers JD, et al "Phase 2 Randomized Controlled Trial of DPP1 Inhibitor Brensocatib (INS1007) in Patients with Bronchiectasis: the WILLOW Study" ATS 2020.