DPP-1 Blocker a Bust in Severe COVID

BARCELONA -- Treatment with an investigational dipeptidyl peptidase-1 (DPP-1) inhibitor failed to improve outcomes in severe COVID-19 and was associated with worsening clinical status and greater mortality, a randomized trial showed.

In the study of over 400 patients, those receiving oral brensocatib had worse clinical status on the World Health Organizations's (WHO) 7-point ordinal scale at 29 days compared to those receiving placebo (adjusted OR 0.72, 95% CI 0.57-0.92), reported Holly R. Keir, PhD, of the University of Dundee in Scotland.

On top of that, deaths were higher in the brensocatib arm (15%) versus the placebo arm (11%), with an adjusted hazard ratio of 1.41 (95% CI 1.06-1.88).

Keir noted that the primary outcome was adjusted for confounders like age, sex, and the fact there were more patients with chronic obstructive pulmonary disease (COPD) in the study arm.

"We still saw that high mortality, so we do believe that the results are real," she said at the European Respiratory Society (ERS) meeting here.

New ventilation use was also greater among patients receiving brensocatib, with an adjusted incidence rate ratio of 1.68 (95% CI 1.09-2.58), according to the findings, which were published simultaneously in Lancet Respiratory Medicine.

"It's a small trial," Keir said. "So there's some caution in interpreting the results."

Brensocatib is a selective, competitive, and reversible inhibitor of DPP-1, which activates neutrophil serine proteases. The investigational treatment has shown promise in reducing chronic lung inflammation for patients with non-cystic fibrosis bronchiectasis.

For COVID, "the rationale was that neutrophil serine proteases are associated with severity and mortality, [and that] reducing them would be beneficial," said Keir.

In an editorial that accompanied the publication of the study, Catharina Conrad, MD, PhD, and Mark R. Looney, MD, both of the University of California San Francisco, described how "neutrophils in people with severe COVID-19 show increased abundance, altered phenotypes, and dysregulated functionality."

Though prior research "supports that oral brensocatib can modulate pulmonary inflammation, it is possible that drug concentrations in the lung were not reached at an early enough timepoint to limit or reverse COVID-19 hyperinflammation," they wrote.

Despite the negative findings, "it cannot be excluded that DPP-1 inhibition might have the potential to help specific patient subgroups when given at the right time," according to Conrad and Looney.

Dubbed STOP-COVID19, the study presented by Keir was a multicenter, double-blind randomized trial conducted at 14 hospitals in the U.K. from June 2020 to January 2021. Within 96 hours of hospitalization, 406 patients were randomized to receive a once-daily dose of brensocatib 25 mg or placebo orally for 28 days, on top of standard care. Randomization was stratified by site and age.

Patients had an average age of 62 years, 59-66% were male, and 88% were white. As noted, more patients in the brensocatib group had COPD (15% vs 10% in the placebo group) though fewer had hypertension (37% vs 42%, respectively) or diabetes with complications (3% vs 7%).

Both groups at baseline began with a mean 7-point WHO scale score of 4, and more than three-fourths needed supplemental oxygen.

For inclusion, patients had to be hospitalized with COVID-19 with at least one risk factor for severe illness. Patients were excluded if they had advanced kidney disease, liver enzyme levels five times the upper limit of normal or a history of severe liver disease, or if they were on treatment for HIV, among other criteria.