STOP-COVID19 trial: brensocatib did not improve the clinical condition of patients with severe SARS-CoV-2 infection

Brensocatib did not improve the clinical status of patients hospitalized with severe SARS-CoV-2 infection in the randomized, double-blind, placebo-controlled, multicenter clinical trial STOP-COVID19, according to research published at the ATS 2022 international conference.

The study, which started in June 2020, took place in 14 UK hospitals, where participants were randomized to receive 25mg per day of brensocatib or a placebo for 28 days. One hundred and ninety patients received brensocatib, while 214 received placebo.

All study patients had confirmed SARS-CoV-2 infection and at least one severe COVID-19 risk factor, such as the need for supplemental oxygen. People on mechanical ventilation were excluded from the study. All participants received standard treatment.

The treatments currently available to treat COVID-19, such as dexamethasone and anti-IL-6 antibodies, reduce inflammation, but their effect is not primarily on neutrophils or neutrophil inflammation. We performed the STOP-COVID trial to test the hypothesis that direct targeting of neutrophilic inflammation by inhibiting dipeptidyl peptidase-1 (DPP1) would provide additional benefits to patients with severe COVID-19 in addition to standard of care.

Holly Keir, PhD, Presenting Author, Postdoctoral Fellow, University of Dundee School of Medicine, Dundee, UK

A severe COVID-19 infection is primarily caused by an excessive and damaging immune response to the virus. A number of different immune cells are involved in this response, including neutrophils. Neutrophils release enzymes and other substances that cause severe lung damage. Studies have consistently shown that high levels of neutrophilic inflammation are associated with poorer outcomes in COVID-19.

Brensocatib is an investigational oral inhibitor of DPP1, an enzyme responsible for the activation of neutrophil serine proteases.

In STOP-COVID19, time to clinical improvement and time to discharge were not different between groups. Mortality was 10.7% and 15.3% in the groups receiving placebo and brensocatib, respectively. The use of oxygen and re-ventilation was also numerically greater in patients treated with brensocatib. Predefined subgroup analyzes based on age, gender, baseline severity, co-medications, and symptom duration supported the primary results. Adverse events were reported in 46.3% of placebo-treated patients and 44.8% of brensocatib-treated patients.

The researchers also conducted a substudy at two study sites to directly measure inflammation in patients receiving DPP1 inhibition or a 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 treatment group and remained significantly lower until day 29.

“Although we did not find a beneficial effect of treatment in this population, these results are important for future efforts to target neutrophil inflammation in the lungs. STOP-COVID19 is the largest completed trial of inhibition of DPP1 in humans and we have performed an extensive characterization of how DPP1 inhibition affects the immune system response,” noted Dr. Keir. “Using advanced proteomics (the study of structures, functions and protein interactions), we have already observed important changes in neutrophils with DPP1 inhibition that will help us better understand the potential role of this treatment in other diseases.”

One such disease is bronchiectasis, where a phase 2 trial published in 2020 showed brensocatib reduced the risk of exacerbations.

The STOP-COVID19 study was an investigator-initiated study, sponsored by the University of Dundee and funded by Insmed Incorporated.

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