Compassionate Use of Remdesivir for Patients with Severe Covid-19

Grein, Jonathan; Ohmagari, Norio; Shin, Daniel B.; Diaz, George A.; Asperges, Erika; Castagna, Antonella; Feldt, Torsten; Green, Gary; Green, Margaret L.; Lescure, François-Xavier; Nicastri, Emanuele; Oda, Rentaro; Yo, Kikuo; Quirós-Roldán, Eugenia; Studemeister, Alex; Redinski, John; Ahmed, Seema; Bernett, Jorge R.; Chelliah, Daniel; Chen, Danny; Chihara, Shingo; Cohen, Stuart H.; Cunningham, John J.; Monforte, Antonella d’Arminio; Saad, Ismail; Kato, Hideaki; Lapadula, Giuseppe; L’Her, Erwan; Maeno, Toshitaka; Majumder, Sumit; Massari, Marco; Mora-Rillo, Marta; Mutoh, Yoshikazu; Nguyen, Duc Trung; Verweij, E.; Zoufaly, Alexander; Osinusi, Anu; DeZure, Adam; Zhao, Yang; Zhong, Lijie; Chokkalingam, Anand P.; Elboudwarej, Emon; Telep, Laura; Timbs, Leighann; Henne, Ilana N.; Sellers, Scott; Cao, Huyen; Tan, Susanna K.; Winterbourne, Lucinda; Desai, Polly; Mera, Robertino M.; Gaggar, Anuj; Myers, Robert P.; Brainard, Diana M.; Childs, Richard W.; Flanigan, Timothy P.

doi:10.1056/nejmoa2007016

Cited by 2,582 publications

(2,838 citation statements)

References 27 publications

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“…A recent trial for favipirivir, demonstrated some success with an improvement over arbidol from 56% to 71% (p = 0.02) in patients without risk factors (but not critical cases or patients with hypertension and/or diabetes) [38]. The results of compassionate use of remdesivir in severely ill patients was also recently reported, and if confirmed in ongoing randomized, placebo-controlled trials will serve as a further validation of the other candidates presented here [39]. The authors are unaware of any ongoing COVID-19 trials for the other 7 candidate molecules with Cmax above their reported EC90, and none were reported on www.clinicaltrials.gov at the time of manuscript submission (14 th April 2020).…”

Section: Discussionsupporting

confidence: 65%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

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Section: Discussionsupporting

confidence: 65%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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“…24 The viral polymerase inhibitor remdesivir holds the greatest promise and it is currently being evaluated in several clinical trials. 25,26 The HIV drug combination lopinavir and ritonavir recently failed in a clinical trial for COVID-19 with no significant therapeutic efficacy was observed. 27 To address this unmet medical need, we initiated a drug repurposing screening to identify potent inhibitors against the SARS-CoV-2 M pro from a collection of FDA-approved protease inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The protease inhibitors are grouped based on their targets and mechanism of action and include proteasome inhibitors (1-8); HIV protease inhibitors (9)(10)(11)(12)(13)(14); γ-secretase inhibitors (15)(16)(17)(18)(19)(20)(21)(22); HCV NS3-4A protease inhibitors (23)(24)(25)(26)(27)(28)(29); DPP-4 inhibitors (30)(31)(32)(33)(34)(35); miscellaneous serine protease inhibitors (36)(37)(38)(39); cathepsin and calpain protease inhibitors (40-43); miscellaneous cysteine protease inhibitors (44-48); matrix metalloprotease inhibitors (49-51); and miscellaneous protease inhibitors (52-55). The inhibitors were pre-incubated with 100 nM of M pro at 30 °C for 30 minutes in the presence of 4 mM 1,4-dithiothreitol (DTT) before the addition of 10 µM FRET substrate.…”

Section: Primary Screening Of a Focused Protease Library Against Thementioning

confidence: 99%

Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

Sacco

Hurst

et al. 2020

Preprint

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A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 , started to circulate among humans around December 2019, and it is now widespread as a global pandemic.The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.4% as of April 15, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M pro ). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, calpain inhibitors II, XII, and MG-132 were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies and thermal shift binding assays. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known M pro inhibitors. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.

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“…The products were characterized by hydrogen nuclear magnetic resonance ( 1 H NMR, Bruker Magnet System, Karlsruhe, Germany, 300 MHz/54 mm) and mass spectrum (MS, Waters LC-MS System, Milford, MA, USA) to confirm the structure and purity. Three dose levels 10, 50, 150 μ g/mouse of the drug were used for intraperitoneal injection (dissolved in sterile saline) once a day (9). The drug was dissolved in saline solution before injection.…”

Section: Drugsmentioning

confidence: 99%

A preliminary study on the reproductive toxicity of GS-5734 on male mice

Fan

Luo

Zhao

et al. 2020

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Background: GS-5734 as a novel and promising medicine for COVID-2019, its biological impact on the mammalian reproductive system has not been systematically studied. The aim of this study was to evaluate the effects of GS-5734 on sperm parameters and spermatogenesis in mice. Materials and Methods:In this study, GS-5734 was synthesized according to the report. 28 adult male mice were randomly segregated into four groups (n=7 for each group). The group 1 was set as the control group, the group 1, 2, 3 and 4 were administered with GS-5734 at a daily dose of 0, 10, 50, 150 μ g/mouse respectively, by intraperitoneal injection for 10 days. On the 7th day after the last injection, the testes and cauda epididymides were collected for HE staining and sperm concentration, motility, morphology analysis. Results:The results indicated that after treated with GS-5734, the total sperm count and motile sperm rate showed downward trends, the abnormal sperm rate showed an increasing trend. As compared with the control group, GS-5734 at a daily dose of 150 μ g/mouse caused a significant decrease in sperm concentration and motility, and a significant increased of abnormal sperm rate; the 50 μ g/mouse drug treatment lead to a significant decrease in sperm motility and an increase in abnormal sperm rate. The HE staining of testicular and epididymal tissues showed that the spermatogenesis of mice was significantly deteriorated with the increasing dosage of GS-5734, especially in the 150 μ g/mouse group. Conclusion:Our findings suggest that a high dosage of GS-5734 may induce testicular toxicity and result in deterioration of sperm parameters in mice. More investigation on the reproductive toxicity of GS-5734 is required.

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Compassionate Use of Remdesivir for Patients with Severe Covid-19

Cited by 2,582 publications

References 27 publications

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

A preliminary study on the reproductive toxicity of GS-5734 on male mice

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