#Ensitrelvir for the #treatment of hospitalized adults with #COVID19: an international phase 3 randomized placebo-controlled trial

 

Abstract

Background

Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity.

Methods

We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the Days to Recovery Scale through Day 60 (DRS-60), analyzed using a Van Elteren test.

Results

From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (p=0.19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; p<0.001). There was no difference in secondary clinical outcomes or pre-specified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively.

Conclusions

Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared to earlier periods in the COVID-19 pandemic, and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

Source: 

Link: https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciag272/8660678?redirectedFrom=fulltext

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Timing of #Remdesivir Initiation and Clinical #Outcomes in Hospitalized Patients with #COVID19 Who Are at High Risk of Disease Progression in #Japan: A Health Insurance Claims Database Study

 

Abstract

Early initiation of remdesivir (RDV) is recommended to improve COVID-19 outcomes, but real-world studies describing patterns of RDV use and related outcomes among Japanese COVID-19 patients at high-risk of severe outcomes or death are limited. This claims-based cohort study included 60,165 high-risk patients hospitalized with COVID-19 between October 2021 and June 2023 using the DeSC Healthcare claims database. Patients were categorized into early-RDV (within 2 days of hospital admission), late-RDV (between day 3 and day 7), and no-RDV groups based on RDV initiation timing. Descriptive analyses were performed according to RDV groups. Of the study patients, ≥85% were very elderly (≥75 years). Approximately 39% of patients received early RDV, 2% received late RDV, and 59% received no RDV. By day 28, the proportion of alive discharge for early-, late-, and no-RDV groups was 74.9%, 63.1%, and 71.8%, respectively. The mortality for early-, late-, and no-RDV groups was 7.7%, 8.8%, and 8.4%, respectively. Future hypothesis-driven studies with an appropriate adjustment for confounders are needed to formally evaluate the impact of RDV initiation timing on clinical outcomes in this high-risk, predominantly late-elderly population in Japan.

Source: 

Link: https://www.mdpi.com/1999-4915/18/4/479

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#Remdesivir as a potent #antiviral against prototype and current #epidemic #Oropouche virus #strains (BeAn19991 and PE-IAM4637)

 

Highlights

• We generated a recombinant reporter OROV that expresses the eGFP fluorescent protein in infected cells.

• We found that remdesivir efficiently inhibited the replication of Oropouche virus (OROV) using this reporter OROV.

• We demonstrated strain-dependent differences in the replication efficiency of OROV.

Abstract

The Oropouche virus (OROV), an orthobunyavirus transmitted by biting midges, is the causative agent of Oropouche fever, which has caused multiple outbreaks in South and Central America. During the most recent epidemic in 2023–2025, more than 25,000 laboratory-confirmed cases were reported in Brazil, and no licensed antivirals have been reported to be effective date. In this study, we generated a recombinant OROV-expressing enhanced green fluorescent protein (rOROV/GFP) to facilitate rapid and sensitive antiviral evaluation. Growth kinetics demonstrated that rOROV/GFP replicated less efficiently than wild-type rOROV and that the historical prototype strain (BeAn19991) exhibited higher replication efficiency than the recent epidemic isolate (PE-IAM4637) in both Vero E6 and Huh7 cells. Using this system, we evaluated the antiviral activity of ribavirin, favipiravir (T-705), and remdesivir against OROV. All three compounds inhibited OROV replication in a dose-dependent manner, with remdesivir showing the greatest potency (IC₅₀ values of 0.31 µM). Taken together, our findings highlight remdesivir as a promising candidate for the treatment of Oropouche fever caused by OROV. Furthermore, we established rOROV/GFP as a powerful tool for antiviral drug screening.

Source: 

Link: https://www.sciencedirect.com/science/article/pii/S0168170225001583?via%3Dihub

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Molecular basis of #SARS-CoV-2 proofreading enzyme–mediated #resistance to #remdesivir

 

Abstract

SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.

Source: Proceedings of the National Academy of Sciences of the United States of America, https://www.pnas.org/doi/full/10.1073/pnas.2519755122

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#Remdesivir: Effectiveness and Safety in Hospitalized #COVID19 #Patients—Analysis of Retrospectively Collected Data from Daily Practice in #Omicron Variant Era and Comparison with the Pre-Omicron Period

 

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has impacted global health. Remdesivir was approved based on clinical trials demonstrating improved outcomes in hospitalized patients. The ReEs-COVID19 study provides real-world evidence on its effectiveness and safety across two periods: Pre-Omicron and Omicron. This retrospective, observational cohort study included 1610 patients hospitalized with COVID-19, treated with remdesivir during Pre-Omicron (September 2020–February 2021; n = 606) and Omicron (June 2022–March 2023; n = 1004) periods. Primary endpoint: time to discharge; Hepatic/renal function abnormalities were also investigated. In the Omicron period patients were older and had more comorbidities but remdesivir was initiated earlier (median: 2 days from symptom onset) compared to the Pre-Omicron period (8 days). ICU admissions rates and direct COVID-19-related deaths were significantly lower, but overall 30-day mortality was higher during the Omicron period. Earlier remdesivir administration was associated with faster discharge. Abnormal liver tests and acute kidney injury were rare across both periods. ReEs-COVID19 confirmed remdesivir’s effectiveness and safety in real-world clinical settings during both periods, underscoring its importance in treatment of hospitalized COVID-19 patients, especially when initiated earlier in the disease course. Further research is needed to evaluate its utility in specific subgroups (e.g., immuno-compromised) and in combination with other treatments.

Source: Microorganisms, https://www.mdpi.com/2076-2607/13/10/2242

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#Marburg Virus #Disease in #Rwanda, 2024 — Public Health and Clinical Responses

 

Abstract

Background

On September 27, 2024, Rwanda reported an outbreak of Marburg virus disease (MVD), after a cluster of cases of viral hemorrhagic fever was detected at two urban hospitals.

Methods

We report key aspects of the epidemiology, clinical manifestations, and treatment of MVD during this outbreak, as well as the overall response to the outbreak. We performed a retrospective epidemiologic and clinical analysis of data compiled across all pillars of the outbreak response and a case-series analysis to characterize clinical features, disease progression, and outcomes among patients who received supportive care and investigational therapeutic agents.

Results

Among the 6340 patients with suspected MVD who underwent testing, 66 had laboratory-confirmed MVD, 51 (77%) of whom were health care workers. The median estimated incubation period was 10 days (interquartile range, 8 to 13), and symptom onset occurred a median of 2 days (interquartile range, 1 to 3) before hospital admission. The results of epidemiologic investigations were highly suggestive of a zoonotic origin of the outbreak: an index patient was identified who had been exposed to Egyptian fruit bats at a mining site. The case fatality rate in the outbreak was 23% (15 deaths among 66 patients). Remdesivir and the monoclonal antibody MBP091 were used under expanded access and clinical trial protocols. In addition, 1710 frontline workers and high-risk contacts received the chimpanzee adenovirus 3–vectored vaccine ChAd3-MARV under emergency use authorization in a phase 2 clinical trial.

Conclusions

Implementation of containment measures, advanced supportive care, and access to investigational countermeasures may have contributed to reduced mortality from MVD in this outbreak. Enhancing surveillance, improving infection prevention and control in health care settings, and ensuring timely deployment of medical countermeasures will be critical for mitigating the effects of future filovirus disease outbreaks.

Source: The New England Journal of Medicine, https://www.nejm.org/doi/full/10.1056/NEJMoa2415816?query=TOC

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#SARS-CoV-2 #Remdesivir Exposure Leads to Different Evolutionary Pathways That Converge in Moderate Levels of Drug #Resistance

Abstract

Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC50). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance.

Source: Viruses, https://www.mdpi.com/1999-4915/17/8/1055

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#Remdesivir, mAb114, REGN-EB3, and #ZMapp partially rescue nonhuman #primates infected with a low passage #Kikwit variant of #Ebola virus

Abstract

In 2018, a clinical trial of four investigational therapies for Ebola virus disease (EVD), known as the PALM trial, was conducted in the Democratic Republic of Congo. All patients received either the antiviral remdesivir (RDV) or a monoclonal antibody product: ZMapp, mAb114 (Ebanga), or REGN-EB3 (Inmazeb). The study concluded that both mAb114 and REGN-EB3 were superior to ZMapp and RDV in reducing mortality from EVD. However, the data suggested that some patients in the RDV and ZMapp groups might have been sicker at the time of treatment initiation. Here, we assessed the efficacy of each of these therapies in a uniformly lethal rhesus monkey model of EVD when treatment was initiated 5 days after Ebola exposure. Treatment with RDV, mAb114, REGN-EB3, and ZMapp each resulted in similar survival (approximately 40%). Survival was associated with circulating viral load at treatment initiation. A trend of more escape mutants in the GP1 and GP2 domains was observed for the mAb114 group. Our data show similar suboptimal efficacy of individual therapeutics in the uniformly lethal NHP model of EVD, supporting further clinical investigation of therapeutic combinations to maximize the overall therapeutic effect and improve patient outcomes, particularly for the treatment of advanced stage EVD.

Source: Nature Communications, https://www.nature.com/articles/s41467-025-59168-5

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Improving #clinical #care of patients in #Nipah #outbreaks: moving beyond ‘compassionate use’

Summary

The 2024 Nipah outbreak in Kerala, India—its fifth in six years—and the recurring annual outbreaks in Bangladesh underscore the persistent threat posed by the Nipah virus (NiV) in the region. With a high mortality rate, human-to-human transmission potential, and the widespread presence of Pteropus bats, the natural reservoir, NiV remains a significant epidemic threat. Despite being a WHO priority pathogen, there has been no systematic effort to improve patient care for NiVD, leading to consistently poor outcomes. Current care relies on supportive measures and the ‘compassionate use’ of unapproved drugs like ribavirin and remdesivir. Drugs used ‘off-label’ during outbreaks can become the ‘standard of care’ without robust evidence of their safety or efficacy, complicating the testing of new therapies and perpetuating uncertainty about their true effectiveness. To improve NiVD care, we propose four key strategies: 1) Enhance early case detection, 2) optimize supportive care to improve outcomes and create a standard for future trials, 3) adopt a syndromic approach centered on encephalitis, and 4) explore innovative trial designs tailored to low case numbers as an alternative to ‘compassionate use’. By integrating these strategies, healthcare systems in NiV-endemic regions will be better equipped to manage both current and future outbreaks.

Source: Lancet Regional Health South-East Asia, https://www.thelancet.com/journals/lansea/article/PIIS2772-3682(24)00177-X/fulltext

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#Remdesivir and #Obeldesivir Retain Potent #Antiviral Activity Against #SARS-CoV-2 #Omicron Variants

Abstract

As new SARS-CoV-2 variants continue to emerge, it is important to evaluate the potency of antiviral drugs to support their continued use. Remdesivir (RDV; VEKLURY®) an approved antiviral treatment for COVID-19, and obeldesivir (ODV) are inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain antiviral activity against the Omicron variants BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in these and previous Omicron variants. Phenotypic analysis of these polymorphisms confirmed no impact on the antiviral activity of RDV or ODV and suggests Omicron variants containing these Nsp12 polymorphisms remain susceptible to both compounds. These data support the continued use of RDV in the context of circulating SARS-CoV-2 variants and the development of ODV as an antiviral therapeutic.

Source: Viruses, https://www.mdpi.com/1999-4915/17/2/168

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