A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19

Kim, So Hyun; Jeon, Seng‐Ho; Kim, Jung-Hee; Koh, Jong Hoon; Won, Seung; Kim, Ji Won; Kim, Yeonjae; Kim, Choon Kwan; Shin, Yun Chul; Kang, Beodeul; Kang, Suna; Park, Chul Hee; Lee, Bo-Young; Lee, Ji Yeon; Lee, Chung Hoon; Choi, Jeongyong; Kim, Jin Yong; Yu, Shi Nae; Peck, Kyong Ran; Kim, Sung-Han; Heo, Jung Yeon; Kim, Hyun ah; Park, Hyunjin; Choi, JoungWon; Han, Jumi; Kim, JooHyun; Kim, Hyoung jun; Han, Se Hee; Yoon, Aeri; Park, MiHee; Park, SuJung; Kim, YuKyung; Jung, Minji; Oh, Myoung Don

doi:10.1128/aac.00452-22

Cited by 15 publications

(10 citation statements)

References 22 publications

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“…The lack of efficacy of camostat on SARS-CoV-2 viral load in the present meta-analysis is in agreement with the findings in previously published RCTs where swab specimens from the nasopharynx or oropharynx were taken. 8,11–14 Regarding the role of TMPRSS2 in viral entry into the cells, it might be thought that the inhibitory effect of camostat may especially be effective in the early phase of COVID-19. SARS-CoV-2 RNA levels peak around symptom onset and then gradually decline, supporting that administration of camostat might best be started as early as possible in the course of infection.…”

Section: Discussionmentioning

confidence: 99%

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Individual Patient Data Meta-Analysis evaluating Camostat Mesilate to Treat COVID-19 in Community Settings

Hedlin,

Tobback,

Lee

et al. 2024

Preprint

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Background: In the COVID-19 pandemic, a number of phase II and III randomized trials were launched to evaluate the effectiveness of camostat, an orally administered TMPRSS2 inhibitor previously approved for other indications, for treating SARS-CoV-2 infections. Owing to the rapidly changing landscape during the pandemic, many of these trials were unable to reach completion. Further, methods for synthesizing data for trials that were launched and not completed were critical. Methods: This study aimed to consolidate global evidence by identifying placebo-controlled, randomized trials of camostat and analyzing their collective clinical and virologic impact on SARS-CoV-2 through an individual participant data meta-analysis. We harmonized data from the included studies and utilized Bayesian statistical models to assess virologic outcomes (measured by the rate of change in viral shedding) and clinical outcomes (based on the time to the first of two consecutive symptom-free days), adjusting for age and sex. Findings: The meta-analysis incorporated data from six countries, totaling 431 patients across the studies; 118 patients contributed data for the primary virologic outcome and 240 for the clinical symptom outcome. Camostat did not improve the rate of change in viral load (difference in rate of change = 0.11 Ct value/day higher, 95% credible interval 2.04 lower to 2.23 higher) or time to symptom resolution (hazard ratio = 0.87, 95% credible interval 0.51, 1.55) when compared to placebo. Interpretation: In a meta-analysis prompted by a fast-changing landscape during the pandemic, we jointly synthesized evidence across multiple trials that did not meet their original recruitment goals. Despite its theoretically promising mode of action, camostat did not demonstrate a statistically significant virologic or clinical benefit in treating COVID-19, highlighting the complexity of drug repurposing in emergency health situations.

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Section: Discussionmentioning

confidence: 99%

“…Consequently, many of the trials investigating camostat stalled and only a few published their findings (Table 1). 8–14 Those that have been published demonstrated inconsistent results, each focusing on different target subgroups with limited ability to draw informative conclusions.…”

Section: Introductionmentioning

confidence: 99%

Individual Patient Data Meta-Analysis evaluating Camostat Mesilate to Treat COVID-19 in Community Settings

Hedlin,

Tobback,

Lee

et al. 2024

Preprint

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“…The plasma concentration–time values of GBPA and GBA were analyzed with Phoenix WinNonlin version 8.3 (Pharsight Corporation, Mountain View, CA, USA). The dosing regimen of the simulation was set to three times a day for 14 days, which was selected based on COVID-19 clinical studies [ 30 ]. The simulation involved 1000 subjects.…”

Section: Methodsmentioning

confidence: 99%

Safety Evaluation and Population Pharmacokinetics of Camostat Mesylate and Its Major Metabolites Using a Phase I Study

Kim,

Moon,

Kim

et al. 2023

Pharmaceutics

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Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information.

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“…Camostat mesylate is an oral SARS-CoV-2 TMPRSS2 inhibitor that showed a good safety profile but no statistically significant reduction in time to clinical improvement in phase II clinical trials for patients with mild-to-moderate COVID-19 (Kim Y S, et al, 2022). It is currently assessed in phase III clinical trials for the indication of severe COVID-19 (Table 2).…”

Section: Host-directed Antiviralsmentioning

confidence: 99%

Therapeutic developments for SARS-CoV-2 infection—Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice

et al. 2023

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This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.

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A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19

Cited by 15 publications

References 22 publications

Individual Patient Data Meta-Analysis evaluating Camostat Mesilate to Treat COVID-19 in Community Settings

Individual Patient Data Meta-Analysis evaluating Camostat Mesilate to Treat COVID-19 in Community Settings

Safety Evaluation and Population Pharmacokinetics of Camostat Mesylate and Its Major Metabolites Using a Phase I Study

Therapeutic developments for SARS-CoV-2 infection—Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice

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