Brensocatib Proves Ineffective for Patients Hospitalized With COVID-19

Patients hospitalized with COVID-19 treated with brensocatib had no improvement in clinical status after 29 days of treatment, according to clinical trial findings published recently in The Lancet Respiratory Medicine.

Increased neutrophil serine protease has been reported in cases of severe and fatal COVID-19 infection. Dipeptidyl peptidase (DDP-1) is the enzyme responsible for neutrophil serine protease activation. Brensocatib is an inhibitor of DPP-1. Researchers sought to discover whether brensocatib would improve patient outcomes among those hospitalized with COVID-19.

Investigators in the United Kingdom conducted a randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trial (ClinicalTrials.gov Identifier: NCT04817332) between June 2020 and January 2021 that included 406 patients aged 16 years and older hospitalized with COVID-19 (confirmed by RT-PCR) with at least 1 risk factor for severe disease. Common comorbidities included hypertension (40%), obesity (22%), and asthma (18%).

Within 4 days of admission, participants were randomly assigned 1:1 to receive 28 days of once-daily brensocatib 25mg or placebo orally. Patients were stratified by age (<65 years or ≥65 years) and site (14 hospitals across the United Kingdom). All patients (88% White British; 38% women; 40% who currently or formerly smoked) continued other therapies necessary to manage their condition. The primary endpoint was patient score on the 7-point WHO ordinal scale for clinical status at day 29 following random assignment.

There were 192 patients assigned to the brensocatib group and 214 to the placebo group. (Notably, 2 patients were subsequently excluded from the brensocatib group and primary endpoint data were unavailable for 3 patients in each group.)

Researchers found worse clinical status at day 29 among patients in the brensocatib group vs those in the placebo group (adjusted odds ratio 0.72; 95% CI, 0.57-0.92). Overall, 185 patients reported at least 1 adverse event (99 [46%] placebo group, 86 [45%] brensocatib group). Gastrointestinal disorders and infections were the most common adverse events.

Researchers found 87% of participants in the placebo group and 84% in the brensocatib group showed clinical improvement; the mortality rate was 11% in the placebo group and 15% in the brensocatib group died. The researchers noted no difference between groups in time to clinical improvement or in time to discharge from hospital. Prespecified subgroup analysis based on sex, baseline severity, co-medications, age, and duration of symptoms supported results of the primary analysis. The researchers also noted that neutrophil elastase levels in the brensocatib group were reduced over 29 days compared with the placebo group.

Trial limitations include patients’ receipt of additional interventions and researchers’ inability to measure neutrophil serine protease activity in bronchoalveolar lavage.

The study authors concluded that “Although multiple studies suggest high amounts of neutrophilic inflammation are associated with worse outcomes in COVID-19, our study does not support targeting neutrophilic inflammation with DPP-1 inhibition as a therapeutic strategy in patients hospitalised with COVID-19.” They added that the worse clinical status found in the brensocatib group suggests “the need for caution in targeting DPP-1 or DPP-1-dependent proteases in patients hospitalised with COVID-19.”

Disclosure: This research was sponsored by the University of Dundee and supported by Insmed, Bridgewater, NJ. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Keir HR, Long MB, Abo-Leyah H, et al.; STOP-COVID19 Investigators. Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. Lancet Respir Med. Published online September 2, 2022. doi:10.1016/S2213-2600(22)00261-2