Source:

Keir HR, et al. A Randomized Double-Blind Placebo-Controlled Trial of Dipeptidyl Peptidase-1 Inhibition in Hospitalized Patients with COVID-19: The STOP-COVID19 Trial. Presented at: American Thoracic Society International Conference; May 13-18, 2022; San Francisco (hybrid meeting).

Disclosures:
This study was funded by Insmed.

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SAN FRANCISCO — Brensocatib, an investigational oral inhibitor of dipeptidyl peptidase 1, did not improve the clinical status of patients hospitalized with severe COVID-19 at 29 days, according to results of the STOP-COVID19 trial.

The randomized, double-blind, placebo-controlled trial included 404 patients hospitalized with severe COVID-19 from June 2020 to February 2021 in 14 hospitals in the U.K. All patients had confirmed SARS-CoV-2 infection with at least one risk factor for severe disease. Patients were randomly assigned to treatment with brensocatib (Insmed) 25 mg per day (n = 190; mean age, 62 years; 40.7% women) or placebo (n = 214; mean age, 62.3 years; 34.2% women) for 28 days. Two-thirds of patients in each treatment group were receiving supplementary oxygen at baseline.

Hospital corridor
Source: Adobe Stock.

“Treatments currently available to treat COVID-19, such as dexamethasone and anti-[interleukin]-6 antibodies, reduce inflammation, but their effect is not primarily on neutrophils or neutrophilic inflammation,” Holly R. Keir, PhD, postdoctoral researcher at the University of Dundee School of Medicine, U.K., said in a related press release. “We performed the STOP-COVID trial to test the hypothesis that directly targeting neutrophilic inflammation by inhibiting dipeptidyl peptidase 1 would provide additional benefits to patients with severe COVID-19 on top of standard care.”

The primary outcome was the 7-point WHO Clinical Status Scale at 29 days. The adjusted OR was 0.72 (95% CI, 0.57-0.92; P = .008) in favor of the placebo group, according to the results. At day 29, outcomes were as follows in those assigned placebo vs. brensocatib:

  • Not hospitalized with no limitations on activities: 18.7% vs. 14.7%
  • Not hospitalized with limitations on activities: 60.3% vs. 58.9%
  • Hospitalized without requiring supplemental oxygen: 5.1% vs. 3.7%
  • Hospitalized with a requirement for supplemental oxygen: 0.5% vs. 3.2%
  • Hospitalized on noninvasive ventilation or high-flow devices: 0.5% vs. 0%
  • Hospitalized on invasive mechanical ventilation or extracorporeal membrane oxygenation: 2.8% vs. 2.6%
  • Death: 10.7% vs. 15.3%

Prespecified subgroup analyses supported the primary results, the researchers reported.

In other results, there was no significant difference in secondary outcomes including time to clinical improvement (HR = 0.87; 95% CI, 0.76-1) and time to hospital discharge (HR = 0.98; 95% CI, 0.84-1.13) between those assigned brensocatib or placebo. Patients assigned brensocatib had numerically greater rates of new oxygen use (1.7 days vs. 1.5 days) and new ventilation use (2.2 days vs. 1.4 days).

No major safety issues were identified during the study, according to the researchers. Adverse events occurred in 44.8% of the brensocatib group compared with 46.3% of the placebo group. Skin disorders and infections were similar between the groups.

Keir and colleagues conducted a substudy at two sites to measure inflammation in patients receiving DPP1 inhibitor or placebo. They observed a strong anti-inflammatory effect of DPP1 inhibition on neutrophil protease enzymes. Active blood neutrophil elastase levels were reduced by day 8 in the brensocatib group and remained significantly lower through day 29, according to the release.

“Although we did not find a beneficial effect of treatment in this population, these results are important for future efforts to target neutrophilic inflammation in the lungs,” Keir said in the release. “STOP-COVID19 is the largest completed trial of DPP1 inhibition in humans and we have performed extensive characterization of how DPP1 inhibition affects the immune system’s response. Using state-of-the-art proteomics … we have already seen important changes in neutrophils with DPP1 inhibition that will help us to better understand the potential role of this treatment in other diseases.”

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