Camostat Mesylate May Reduce Severity of Coronavirus Disease 2019 Sepsis: A First Observation

Abstract

Objectives: Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown. Design: Retrospective observational case series. Setting: Patient treated in ICU of University hospital Göttingen, Germany. Patients: Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU. Interventions: Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group). Measurements and Main Results: Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation. Conclusions: The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.

Camostat mesylate against SARS‐CoV‐2 and COVID‐19—Rationale, dosing and safety

“…These clinical trials are running in Denmark (CamoCO‐19, NCT04321096), USA (RECOVER, NCT04470544, NCT04353284, NCT04524663, NCT04374019), UK (NCT04455815), Mexico (NCT04530617), Israel (COSTA, NCT04355052), Germany (NCT04338906), South Korea (NCT04521296) and Japan (NCT04451083) and should provide valuable insight into the potential utility of camostat mesylate in treating COVID‐19. A recent open‐label case‐control study with camostat mesylate on COVID‐19 intensive care patients shows promise for these ongoing trials 58 …”

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

“…An alternative and probably safer, versus ACE2 inhibition, approach would be the use of TMPRSS2 inhibitors. TMPRSS2 is druggable and camostat mesylate partially blocked SARS-CoV-2 cell infection [ 4 ] while preliminary reports showed that it reduced the severity of COVID-19 sepsis [ 86 ]; thus, several clinical trials are currently ongoing to test whether camostat mesylate could be repurposed and utilized to combat the current pandemic [ 87 ]. TMPRSS2 inhibition could also reduce viral tropism at the initial site of SARS-CoV-2 infection and enhance anti-viral humoral immune responses of the host [ 88 , 89 ].…”

Closing the portal to SARS-CoV-2 cellular entry: May open newer avenues…

“… Akin to Kumar and colleagues, the essential role of transmembrane protease serine 2 (TMPRSS2) co-expression in mediating the SARS-CoV-2 cellular entry, has captivated the attention of the fraternity [3] , [4] , [5] , [6] . In this context, the TMPRSS2 inhibitors such as camostat mesylate (CM) and nafamostat mesylate (NM) are being currently envisaged as promising repurposed drugs (approved for treating pancreatitis in Japan) in COVID-19 for their anti-inflammatory and antiviral properties owing to serine protease inhibition and resultant viral cellular entry block [3] , [4] , [5] , [6] . A few researchers cite an incremental value to the therapeutic inclusion of a critical host factor blocker like TMPRSS2 inhibitor over an isolated antiviral regimen, in conferring a subsequent resilience to the rapidly developing viral resistance.…”

“…They opine that the isolated viral point mutations are unlikely to accommodate for such a critical host component block [7] . A recent retrospective observational case-series by Hofmann-Winkler et al outlined an attenuation of the COVID-19 disease severity marked by lower sepsis-related organ failure assessment (SOFA) scores paralleled by an ameliorated inflammatory profile in the six ICU patients who received CM compared to the five ICU patients treated with hydroxychloroquine [3] . The maximum CM dose administered in their evaluation amounted to 2 × 100 mg pills three times daily for 5 days which was in accordance with the protocol of a large Denmark randomized controlled trial (RCT, CamoCo-19, NCT04321096).…”

“…Akin to Kumar and colleagues, the essential role of transmembrane protease serine 2 (TMPRSS2) co-expression in mediating the SARS-CoV-2 cellular entry, has captivated the attention of the fraternity [3] , [4] , [5] , [6] .…”