Israel’ RedHill Biopharma is developing an experimental drug, upamostat, to treat COVID-19 infection caused by the SARS-CoV-2 coronavirus and running mild-to-moderate in ambulatory patients.
Oral upamostat has been successfully tested clinically in a small patient population, confirming that it has the potential to eliminate the risk of COVID-19 complications followed by hospitalization or death.
More clinical data needs to be collected to make an unconditional decision on the therapeutic efficacy of upamostat against COVID-19.
In parallel, RedHill is working on an experimental oral drug, opaganib, which focuses on the treatment of COVID-19 occurring severely in hospitalized patients.
Oral opaganib will reduce the likelihood of death and accelerate recovery in hospitalized patients with COVID-19.
Upamostat: Efficacy and Safety of COVID-19 Treatment
The ongoing NCT04723537 phase 2/3 (randomized, double-blind, placebo-controlled, multicenter) clinical trial is evaluating the efficacy and safety of upamostat in the treatment of adult patients with symptomatic COVID-19 infection caused by SARS-CoV-2 coronavirus that occurs in a mild-to-moderate severity and does not require hospitalization.
Among the main inclusion criteria for the trial: manifestation of symptoms or diagnosis of the disease by PCR testing at least 5 days before treatment; oxygen saturation ≥ 92%.
Participants receive upamostat (200 or 400 mg) or placebo once daily for 14 days.
The results of Part A of phase 2 clinical trial (n=61) were as follows:
- Administration of upamostat was associated with a 100% reduction in risk of hospitalization for COVID-19 complications: 0% of patients (n=0/41) in the upamostat group were hospitalized — versus 15% of patients (n=3/20) in the placebo group (p=0.0317).
- Use of upamostat was mirrored by an 88% reduction in the likelihood of developing new severe COVID-19 symptoms: 2.4% of patients (n=1/41) in the upamostat group experienced such events — vs. 20.0% (n=4/20) in the placebo group (p=0.036).
- The safety profile of upamostat was characterized by acceptable tolerability and no serious adverse reactions.
The patient populations in the groups were said to be well balanced in terms of baseline disease severity, risk factors, and vaccination status. The most common variant of coronavirus was Delta: in two-thirds of the subjects (62.5%).
Upamostat Against COVID-19: What’s Next
Part B of phase 2 clinical trial NCT04723537 examines the efficacy and safety of upamostat at the dose that demonstrated adequate therapeutic efficacy in Part A.
The primary efficacy endpoint is set by the time it took to recover.
Secondary endpoints included the following: risk of pneumonia, need for hospitalization, or death from any cause; seroconversion; time to resolution of selected COVID-19 symptoms; development of new symptoms; and changes in biochemical measures of disease severity (oxygen saturation, C-reactive protein, lymphocyte count, cardiac troponin, D-dimer).
Upamostat: Mechanism of Action
Oral upamostat (RHB-107, WX-671) is an inhibitor of serine proteases, enzymes that catalyze protein proteolysis via peptide bond hydrolysis.
In the context of COVID-19 infection, the role of upamostat is to inhibit the activity of transmembrane serine protease 2 (TMPRSS2), which is used by the SARS-CoV-2 coronavirus in preparing the S protein for entry into target cells. TMPRSS2 is required for proteolytic priming of the S protein for subsequent fusion of the viral and cell membranes.    
Since upamostat is targeted to the host target, there is a high probability that coronavirus mutations (they mostly affect the S protein) will not impact the therapeutic efficacy of the drug, including in the task of counteracting the Omicron variant. However, there are concerns that the efficacy of upamostat against Omicron will be reduced because this variant relies more on the transmembrane angiotensin-converting enzyme 2 (ACE2), which, expressed on host cells, serves as the main entry point for the virus.   
Upamostat, formerly known as Mesupron, was licensed from Germany’s Heidelberg Pharma in late June 2014 for $1 million upfront plus a subsequent royalty on sales of the finished drug. The exclusive license covers the entire world except for China, Hong Kong, Taiwan, and Macau. At the time, Heidelberg was called Wilex.
Initially, upamostat was developed for the treatment of cancer: the inhibition of urokinase-type plasminogen activator (uPA, urokinase) — a serine protease involved in the degradation of the extracellular matrix, migration and proliferation of tumor cells — provides inhibition of tumor growth and metastasis.
Upamostat also exhibits inhibitory activity against trypsin-3, trypsin-2, trypsin-1, matriptase-1, and trypsin-6. Suppression of trypsin-3 may be useful in the treatment of inflammatory diseases of the digestive system (irritable bowel syndrome, inflammatory bowel disease, pancreatitis) and trypsin-2 in the treatment of inflammatory lung diseases (acute respiratory distress syndrome [ARDS], chronic obstructive pulmonary disease [COPD], alpha-1 antitrypsin deficiency [A1AD, AATD]).