| |
Antiviral remdesivir prevents disease
progression in monkeys with COVID-19
|
| |
| |
Study supports clinical testing under way across U.S.
Download the PDF here
https://www.nih.gov/news-events/news-releases/antiviral-remdesivir-prevents-disease-progression-monkeys-covid-19
"Remdesivir is the first antiviral treatment with proven efficacy against SARS-CoV-2 in an animal model of COVID-19. Remdesivir treatment in rhesus macaques infected with SARS-CoV-2 was highly effective in reducing clinical disease and damage to the lungs. The remdesivir dosing used in rhesus macaques is equivalent to that used in humans; however, due to the acute nature of the disease in rhesus macaques, it is hard to directly translate the timing of treatment used to corresponding disease stages in humans. In our study, treatment was administered close to the peak of virus replication in the lungs as indicated by viral loads in bronchoalveolar lavages and the first effects of treatment on clinical signs and virus replication were observed within 12 hours. The efficacy of direct-acting antivirals against acute viral respiratory tract infections typically decreases with delays in treatment initation18. Thus, remdesivir treatment in COVID-19 patients should be initiated as early as possible to achieve the maximum treatment effect."
The bioavailability and protective effect of remdesivir in the lungs of infected rhesus macaques supports treatment of COVID-19 patients with remdesivir. Data from clinical trials in humans are pending, but our data in rhesus macaques indicate that remdesivir treatment should be considered as early as clinically possible to prevent progression to severe pneumonia in COVID-19 patients.
Friday, April 17, 2020
What
Early treatment with the experimental antiviral drug remdesivir significantly reduced clinical disease and damage to the lungs of rhesus macaques infected with SARS-CoV-2, the coronavirus that causes COVID-19, according to National Institutes of Health scientists.
The study was designed to follow dosing and treatment procedures used for hospitalized COVID-19 patients being administered remdesivir in a large, multi-center, clinical trial led by NIH's National Institute of Allergy and Infectious Diseases (NIAID). The scientists posted the work(link is external) on the preprint server bioRxiv. The findings are not yet peer-reviewed and should not be considered clinical advice, but are being shared to assist the public health response to COVID-19. A study detailing the development of the rhesus macaque model of mild- to-moderate human disease, conducted by the same team of NIAID scientists, was posted to bioRxiv(link is external) on March 21.
The current study of remdesivir, a drug developed by Gilead Sciences Inc. and NIAID-supported investigators, involved two groups of six rhesus macaques. One group of monkeys received remdesivir and the other animals served as an untreated comparison group. Scientists infected both groups with SARS-CoV-2. Twelve hours later the treatment group received a dose of remdesivir intravenously, and then received a daily intravenous booster dose thereafter for the next six days. The scientists timed the initial treatment to occur shortly before the virus reached its highest level in the animals' lungs.
Twelve hours after the initial treatment, the scientists examined all animals and found the six treated animals in significantly better health than the untreated group, a trend that continued during the seven-day study. They report that one of the six treated animals showed mild breathing difficulty, whereas all six of the untreated animals showed rapid and difficult breathing. The amount of virus found in the lungs was significantly lower in the treatment group compared to the untreated group, and SARS-CoV-2 caused less damage to the lungs in treated animals than in untreated animals.
The investigators note that the data supports initiating remdesivir treatment in COVID-19 patients as early as possible to achieve maximum treatment effect. The authors, from NIAID's Rocky Mountain Laboratories in Hamilton, Montana, also note that while remdesivir helped prevent pneumonia, it did not reduce virus shedding by the animals. "This finding is of great significance for patient management, where a clinical improvement should not be interpreted as a lack of infectiousness," they write.
Article
B. Williamson, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2(link is external).
Who
Emmie de Wit, Ph.D., and Marshall Bloom, M.D., from NIAID's Laboratory of Virology are available to comment on this study.
-------------------
Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2
Brandi N. Williamson1, MPH; Friederike Feldmann2, AS; Benjamin Schwarz3, PhD; Kimberly Meade-White1, MSc; Danielle P. Porter5, PhD; Jonathan Schulz1, BSc; Neeltje van Doremalen1, PhD; Ian Leighton, BA3; Claude Kwe Yinda1, PhD; Lizzette Pérez-Pérez1, MSc; Atsushi Okumura1, DVM; Jamie Lovaglio2, DVM; Patrick W. Hanley2, DVM; Greg Saturday2, DVM; Catharine M. Bosio3, PhD; Sarah Anzick4, PhD; Kent Barbian4, MSc; Tomas Cihlar5, PhD; Craig Martens4, PhD; Dana P. Scott2, DVM; Vincent J. Munster1, PhD; Emmie de Wit1*, PhD
1Laboratory of Virology, 2Rocky Mountain Veterinary Branch, 3Laboratory of Bacteriology and 4Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States of America; 5Gilead Sciences, Foster City, CA, United States of America
Abstract
Background Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection.
Methods To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy.
Results In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and t
here was a clear reduction in damage to the lung tissue.
Conclusions Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.
Competing Interest Statement
The authors affiliated with Gilead Sciences are employees of the company and own company stock. The authors affiliated with NIH have no conflict of interest to report.
Discussion
Remdesivir is the first antiviral treatment with proven efficacy against SARS-CoV-2 in an animal model of COVID-19. Remdesivir treatment in rhesus macaques infected with SARS-CoV-2 was highly effective in reducing clinical disease and damage to the lungs. The remdesivir dosing used in rhesus macaques is equivalent to that used in humans; however, due to the acute nature of the disease in rhesus macaques, it is hard to directly translate the timing of treatment used to corresponding disease stages in humans. In our study, treatment was administered close to the peak of virus replication in the lungs as indicated by viral loads in bronchoalveolar lavages and the first effects of treatment on clinical signs and virus replication were observed within 12 hours. The efficacy of direct-acting antivirals against acute viral respiratory tract infections typically decreases with delays in treatment initation18. Thus, remdesivir treatment in COVID-19 patients should be initiated as early as possible to achieve the maximum treatment effect.
Despite the lack of obvious respiratory signs and reduced virus replication in the lungs of remdesivir-treated animals, there was no reduction in virus shedding. This finding is of great significance for patient management, where a clinical improvement should not be interpreted as a lack of infectiousness. While our study demonstrates the presence of remdesivir metabolites in the lower respiratory tract, the drug levels in upper respiratory tract have not been characterized and novel formulations with alternative route of drug delivery should be considered to improve the distribution to the upper respiratory tract, thereby reducing shedding and the potential transmission risk. However, since severe COVID-19 disease is a result of virus infection of the lungs, this organ is the main target of remdesivir treatment. The bioavailability and protective effect of remdesivir in the lungs of infected rhesus macaques supports treatment of COVID-19 patients with remdesivir. Data from clinical trials in humans are pending, but our data in rhesus macaques indicate that remdesivir treatment should be considered as early as clinically possible to prevent progression to severe pneumonia in COVID-19 patients.
Introduction
Effective treatments for COVID-19 are urgently needed. While a large number of investigational as well as approved and repurposed drugs have been suggested to have utility for treatment of COVID-19, preclinical data from animal models can guide a more focused search for effective treatments in humans by ruling out treatments without proven efficacy in vivo. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1, including against coronaviruses2, that is currently investigated in COVID-19 clinical trials worldwide, including in China, the US and Europe (summarized in3). In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,4,5 In vitro, remdesivir inhibited replication of SARS-CoV-2.6,7 Moreover, in vitro experiments have shown that mutations conferring resistance to remdesivir do not easily emerge in coronaviruses8. Here, we investigated the efficacy of remdesivir treatment in our recently established rhesus macaque model of SARS-CoV-2 infection. In this model, infected rhesus macaques develop mild to moderate, transient respiratory disease with pulmonary infiltrates visible on radiographs, and a shedding pattern similar to that observed in COVID-19 patients9. Therapeutic treatment of rhesus macaques with remdesivir shortly before the peak of virus replication resulted in a significant clinical improvement, reduction in pulmonary infiltrates, and a reduction in pulmonary pathology.
Concentrations of metabolite GS-441524 were determined in lung tissue collected from each lung lobe on 7 dpi, 24 hrs after the last remdesivir treatment was administered and was readily detectable in all remdesivir-treated animals. GS-441524 was generally distributed amongst all six lobes of the lung (Fig S1B). GS-704277 was not detected in the lung tissue. While the pharmacologically active metabolite of remdesivir is the triphosphate of GS-441524, lung homogenate samples spiked with the triphosphate metabolite demonstrated rapid decay of the metabolite in this matrix (data not shown). GS-441524 levels were taken as a surrogate for tissue loading and suggest that the current dosing strategy delivered drug metabolites to the sites of SARS-CoV-2 replication in infected animals.
Lack of respiratory disease in rhesus macaques infected with SARS-CoV-2 and treated with remdesivir
After inoculation with SARS-CoV-2, the animals were assigned a daily clinical score based on a pre-established scoring sheet in a blinded fashion. Twelve hours after the first remdesivir treatment, clinical scores in remdesivir-treated animals were significantly lower than in control animals receiving vehicle solution. This difference in clinical score was maintained throughout the study (Fig. 1A). Only one of the six remdesivir-treated animals showed mild dyspnea, whereas tachypnea and dyspnea were observed in all vehicle-treated controls (Table S1). Radiographic pulmonary infiltrates are one of the hallmarks of COVID-19 in humans. Radiographs taken on 0, 1, 3, 5, and 7 dpi showed significantly less lung lobe involvement and less severe of pulmonary infiltration in animals treated with remdesivir as compared to those receiving vehicle (Fig. 1B and C).
Reduced virus replication in the lower, but not upper respiratory tract after remdesivir treatment
On 1, 3 and 7 dpi BAL were performed as an indicator of virus replication in the lower respiratory tract. Although viral loads in BAL were reduced in remdesivir-treated animals this difference was not statistically significant (Fig. 2A). However, 12 hours after the first remdesivir treatment was administered, the infectious virus titer in BAL was ~100-fold lower in remdesivir-treated animals than controls. By 3 dpi, infectious virus could no longer be detected in BAL from remdesivir-treated animals, whereas virus was still detected in BAL from four out of six control animals (Fig. 2B). Despite this reduction in virus replication in the lower respiratory tract, neither viral loads nor infectious virus titers were reduced in nose, throat or rectal swabs collected from remdesivir-treated animals, except a significant difference in virus titer in throat swabs collected on 1 dpi and in viral loads in throat swabs collected on 4 dpi (Fig. 3).
Decreased viral loads in lungs after remdesivir treatment
All animals were euthanized on 7 dpi. Tissue samples were collected from each lung lobe to compare virus replication in remdesivir-treated and vehicle-treated control animals. In 10 out of 36 lung lobe samples collected from remdesivir-treated animals, viral RNA could not be detected, whereas this was the case in only 3 out of 36 lung lobes collected from control animals. In general, comparison across individual lung lobes in the two groups showed lower geometric mean of viral RNA in remdesivir-treated group (Fig. 4A). Taken together, the viral load was significantly lower in lungs from remdesivir-treated animals than in vehicle-treated controls (Fig. 4B). Virus could be isolated from lung lobes of five out of six vehicle-treated control animals, but none of the lung tissue collected from remdesivir-treated animals was positive in virus isolation. Although fewer tissues from other positions in the respiratory tract were positive by qRT-PCR in remdesivir-treated animals, these differences were not statistically significant (Fig. 4C).
Reduced pneumonia after remdesivir treatment
At necropsy on 7 dpi, lungs were assessed grossly for presence of lesions. Gross lung lesions were observed in one out of six remdesivir-treated animals. In contrast, all six vehicle controls had visible lesions, resulting in statistically significantly difference in the area of the lungs affected by lesions (Fig. 5A, B and Fig. 6A, B). This difference was also evident when calculating the lung weight to bodyweight ratio as an indicator of pneumonia, with a statistically significantly lower ratio observed in remdesivir-treated compared to vehicle-treated animals (Fig. 5C). Histologically, there was a clear effect of remdesivir treatment on lung lesions, with fewer and less severe lesions in the remdesivir animals than in vehicle-treated controls. Histologic lung lesions were absent in three of six remdesivir-treated animals; the three remaining animals developed minimal pulmonary pathology. Lesions in these animals were characterized as widely separated, minimal, interstitial pneumonia frequently located in subpleural spaces (Fig. 6C, E). Five out six vehicle-treated animals developed multifocal, mild to moderate, interstitial pneumonia (Fig. 6D, F). Viral antigen was detected in all animals regardless of treatment (Fig. 6G, H).
Absence of resistance mutations
Deep sequencing was successful on samples from all remdesivir-treated animals and vehicle controls. Known mutations in the RNA dependent RNA polymerase that confer resistance to remdesivir in coronaviruses8 were not detected in any of the samples tested (Table S2).
|
|
| |
| |
|
|
|
