Serine protease inhibition shows promise in COVID-19

The serine protease inhibitor upamostat appears to be beneficial in the treatment of COVID-19 outpatients, being generally tolerable and bringing a rapid resolution of severe symptoms while reducing the incidence of new ones, according to the results of a pilot study.

“The primary objective of this study, determination of the safety and tolerability of upamostat in patients with COVID-19, was met; both [200- and 400-mg once-daily doses] were very well tolerated. There was no effect on liver, renal, or hematologic parameters,” the investigators said.

They also noted improvements in several parameters suggesting that upamostat may be useful in the treatment of COVID-19. For example, compared with placebo-treated patients, upamostat recipients achieved earlier resolution of symptoms.

“Similarly, the decrease in new severe symptoms in upamostat recipients as compared to placebo recipients was quite marked. The absence of hospitalizations for COVID-19 among upamostat-treated patients paralleled the decrease in severe symptoms and the absence of new severe respiratory symptoms among these patients, further suggesting that this was not just a random finding but rather a treatment effect,” the investigators pointed out.

The pilot study included 61 SARS-CoV-2 patients (mean age 45.67 years, 44 percent male) with ≥2 moderate-severe symptoms, with onset within 5 days. Of these, 36 patients (59 percent) had one or more high-risk comorbidities, including hypertension, diabetes, and obesity. Nine patients (15 percent) had received at least one dose of COVID-19 vaccine, and seven (12 percent) were given monoclonal antibody infusions at the start of study treatment. [Int J Infect Dis 2022;doi:10.1016/j.ijid.2022.12.003]

All patients were randomized to receive upamostat at either 200 mg (n=20) or 400 mg (n=21) or placebo (n=20), administered orally daily for 14 days, with 54 patients (89 percent) taking the full course of treatment.

Across treatment groups, the overall frequency of new symptoms of any grade was similar. However, significantly fewer patients in the combined upamostat groups than in the placebo group developed new severe symptoms (2.4 percent vs 20 percent; p=0.036). Only a single patient who received upamostat 400 mg had a drug-related adverse event, which was a mild skin rash. None of the patients discontinued treatment due to a drug-related adverse event.

Recovery from severe symptoms occurred at a median of 8 days with placebo, 4 days with upamostat 200 mg, and 3 days with 400 mg. Furthermore, none of the patients on upamostat were hospitalized for worsening COVID-19 as opposed to three patients on placebo (p=0.03).

“Mean D-dimer levels remained constant over the course of the study in the placebo group but decreased by 38 percent and 48 percent in the upamostat 200 mg and 400 mg groups, respectively. Taken together, these data suggest a modest anticoagulant effect of treatment, a potentially beneficial property in patients with COVID-19,” according to the investigators.

“These data strongly support a larger, pivotal trial of upamostat for treatment of symptomatic outpatients with COVID-19,” they added.

A prodrug of WX-UK1, upamostat was initially expected to function as a thrombin antagonist but later found to inhibit urokinase plasminogen activator, trypsins, and several other serine proteases. The drug has high oral bioavailability and is converted intracellularly to WX-UK1. In tissue analyses, substantial levels of WX-UK1 remain for at least 3 days after oral dosing. [AACR-NCI-EORTC 2017, abstract B055; Breast Care 2008;3:20-24; J Med Chem 1997;40:3091-3099]