Upamostat: a serine protease inhibitor for antiviral, gastrointestinal, and anticancer indications

ABSTRACT

Introduction

Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes.

Areas covered

Research over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months.

Expert opinion

Upamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.

KEYWORDS:

• Antiviral
• COVID-19
• irritable bowel syndrome
• PAR2
• serine protease inhibitor
• trypsin
• upamostat

Article highlights

• Upamostat is a prodrug of WX-UK1, a broad-spectrum serine protease inhibitor was initially developed as a urokinase plasminogen activator (uPA) inhibitor

• Further study demonstrated that it is most active against trypsin isoenzymes, especially trypsin-3, with a Ki = 19 nM

• Upamostat was well tolerated clinically at a daily dose of 400 mg, resulting in tissue levels of WX-UK1 several-fold higher than the Kis for sensitive proteases

• Incidences of mild PTT and INR elevations were greater in upamostat-treated patients than in controls, with no evidence of increased bleeding

• In a small pilot study in outpatients with COVID-19, upamostat-treated patients had more rapid resolution of severe symptoms and no hospitalizations for worsening COVID-19

Declaration of interest

Drs Plasse and Fathi and Ms Fehrmann are paid consultants to RedHill Biopharma. Dr McComsey was an investigator in the COVID-19 study cited above; her participation in the COVID-19 study but not in preparation of the manuscript was funded by RedHill Biopharma.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The writing of this manuscript was funded by RedHill Biopharma, Ltd, Tel Aviv, Israel.