Camostat mesylate therapy in critically ill patients with COVID-19 pneumonia

Sakr, Yasser; Bensasi, Hatim; Ahmed, Taha; Bauer, Michael; Ismail, Khaled M.; Belhaj, Ghazala; Afet, Khaled M.; Munde, Dnyanwshwar; Monk, David; Buschbeck, Samuel

doi:10.1007/s00134-021-06395-1

Cited by 23 publications

(21 citation statements)

References 6 publications

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“…[6][7][8][9][10][11][12][13] Furthermore, a smallscale retrospective study suggested a potential therapeutic effect of camostat mesilate in patients admitted to an intensive care unit. 21 Despite promising results of preclinical studies, as well as a small retrospective study, the results of our study indicate that camostat mesilate is no more effective than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. The lack of antiviral effect was demonstrated based on the median time to the first two consecutive SARS-CoV-2 negative tests (the primary endpoint) and the other clinical outcomes, with no statistically significant or clinically relevant differences between the two groups.…”

Section: Discussioncontrasting

confidence: 62%

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Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Kinoshita

Shinoda

Nisizaki

et al. 2022

Preprint

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Background: In vitro drug-screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). Methods: This was a phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. Findings: One-hundred and fifty-five patients were randomised to receive camostat mesilate (n=78) or placebo (n=77). The median time to the first test was 11 days in both groups, and conversion to negative status was observed in 60.8% and 63.5% of patients in the camostat mesilate and placebo groups, respectively. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. Interpretation: Camostat mesilate is no more effective, based on upper airway viral clearance, than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. Funding: Ono Pharmaceutical Co., Ltd.

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Section: Discussioncontrasting

confidence: 62%

“…6–13 Furthermore, a small-scale retrospective study suggested a potential therapeutic effect of camostat mesilate in patients admitted to an intensive care unit. 21…”

Section: Discussionmentioning

confidence: 99%

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Kinoshita

Shinoda

Nisizaki

et al. 2022

Preprint

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“…The pharmacological inhibition of TMPRSS2 using serine protease inhibitors, such as camostat and nafamostat, has been proposed as a pharmacological treatment of COVID-19 patients. In vitro [12] and animal studies have demonstrated that camostat can block viral entry (reviewed in [52] ), and initial reports on the repurposing of camostat in COVID-19 patients have provided promising results [53] . However, a recently completed clinical trial using camostat in patients hospitalized for severe COVID-19, did not demonstrate a significant reduction in time-to-clinical improvement compared to placebo [54] .…”

Section: Discussionmentioning

confidence: 99%

A common TMPRSS2 variant has a protective effect against severe COVID-19

David¹,

Parkinson²,

Peacock³

et al. 2022

Current Research in Translational Medicine

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Background : The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection. Methods : We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2 V160M ). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M to promote viral entry. Results : We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3 × 10 −3 ). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. Conclusion : TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

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“…Despite its instability in vivo, more recent pharmacological analyses confirmed camostat mesylate as a potential treatment option for COVID-19, because its metabolites, 4-(4-guanidinobenzoyloxy) phenylacetic acid (GBPA) and 4-guanidoninobenzoic acid (GBA), still work as active-site inhibitors and are nearly equal in suppressing authentic SARS-CoV-2 infection in cells derived from human airway epithelia [63,64]. Although the therapeutic benefit of camostat mesylate was already observed in a retrospective analysis of critically ill patients with COVID-19 admitted to the intensive care unit (ICU) of Al Ain Hospital, Abu Dhabi, United Arabs Emirates in March 2020 [65], the recent outcomes of an investigatorinitiated trial in patients hospitalized with COVID-19 do not confirm camostat mesylate as an effective treatment for hospitalized COVID-19 patients [66]. However, an effect of higher doses in the early phase of COVID-19, lowering the risk of disease progression, was not excluded.…”

Section: Protease Inhibitors As a Potential Therapy For Covid-19mentioning

confidence: 99%

Protease Inhibition—An Established Strategy to Combat Infectious Diseases

Sojka

Šnebergerová

Robbertse

2021

IJMS

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Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays—malaria and COVID-19.

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Camostat mesylate therapy in critically ill patients with COVID-19 pneumonia

Cited by 23 publications

References 6 publications

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

A common TMPRSS2 variant has a protective effect against severe COVID-19

Protease Inhibition—An Established Strategy to Combat Infectious Diseases

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