Brensocatib has no impact on COVID-19 clinical outcomes

Results of the STOP-COVID trial, presented at ERS 2022, showed no clinical outcome benefit with the dipeptidyl peptidase-1 (DPP-1) inhibitor brensocatib compared with placebo in patients hospitalized with COVID-19 in the UK.

“[T]reatment with brensocatib for 28 days was associated with a worse clinical status on the WHO* 7-point ordinal scale at the end of treatment than was placebo,” said the researchers.

This multicentre, double-blind trial involved 406 patients aged ≥16 years (mean age 62 years) who were hospitalized with confirmed or clinically suspected SARS-CoV-2 infection and had ≥1 risk factors for severe disease. Within 96 hours of hospitalization, they were randomized 1:1 to receive oral brensocatib (25 mg; n=190) or placebo (n=214) QD for 28 days plus other therapies.

There was a greater proportion of male participants in the brensocatib vs placebo group (66 percent vs 59 percent). Forty-nine and 46 percent of patients in the brensocatib and placebo group, respectively, were never smokers. The most common comorbidities in the brensocatib and placebo groups were hypertension (37 and 42 percent, respectively), obesity (22 percent each), chronic cardiac disease (18 and 17 percent, respectively), and asthma (18 percent each).

During hospitalization, 81 and 80 percent of patients in the brensocatib and placebo group, respectively, received low-dose dexamethasone, 25 and 24 percent, respectively, remdesivir, and 4 and 3 percent, respectively, tocilizumab.

At day 29, patients who received brensocatib had worse clinical status, based on the 7-point WHO ordinal scale for clinical status, than those who received placebo (59 percent vs 60 percent were not hospitalized but had limitations on activities; adjusted odds ratio [OR], 0.72, 95 percent confidence interval [CI], 0.57–0.92; p=0.0077). [ERS 2022, session ALERT 3: COVID and interstitial lung diseases; Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00261-2]

The results of the primary outcome were consistent across all subgroups assessed in the prespecified subgroup analysis.

Clinical improvement (time between randomization and the first day with ≥1-point improvement on the WHO ordinal scale) occurred in 84 and 87 percent of patients in the brensocatib and placebo group, respectively (adjusted hazard ratio [adjHR], 0.87). Time to discharge from hospital or national early warning score (NEWS) ≤2 was comparable between groups (adjHR, 0.98).

The median number of oxygen support-free days was 24.0 and 24.5 days in the brensocatib and placebo groups, respectively. New requirement for supplemental oxygen among hospitalized patients who did not require oxygen at baseline was comparable between groups. Among patients who did not require ventilation at baseline, patients on brensocatib were more likely than those on placebo to require ventilation (adjusted incidence rate ratio, 1.13), though there was no significant between-group difference in terms of ventilation-free days.

Adverse events (AEs) occurred at a comparable rate between the brensocatib and placebo groups (45 percent vs 46 percent; OR, 0.94; p=0.77), while 21 and 16 percent, respectively, experienced serious AEs (IRR, 1.27; p=0.30). Nineteen and 16 percent of patients in the brensocatib and placebo groups, respectively, discontinued trial treatment, mainly due to participant choice or AEs. The most common AEs in both groups were gastrointestinal disorders (9 percent vs 14 percent) and infections and infestations (16 percent vs 15 percent). Fourteen and 11 serious AEs in the brensocatib and placebo groups, respectively, were related to infections and infestations. There were 29 and 23 deaths in the brensocatib and placebo groups, respectively (15 percent vs 11 percent; adjHR, 1.41), over the 28-day follow-up period, though only one death in the placebo group was deemed related to study drug.

“[O]ur study does not support targeting neutrophilic inflammation with DPP-1 inhibition as a therapeutic strategy in patients hospitalized with COVID-19. The worse clinical status in the brensocatib group suggests the need for caution in targeting DPP-1 or DPP-1-dependent proteases in patients hospitalized with COVID-19,” said the researchers.

However, the researchers did not rule out the possibility that the results were a “chance finding”, based on previous studies on tocilizumab or dexamethasone in COVID-19 which were initially negative but were later found to be effective in larger trials or certain subgroups.