Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

Abstract

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium’s antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.Significance statementSARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.

Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials

“…One study was originally included, but was later retracted due to concerns about data integrity, and thus was excluded [42]. Antiviral treatments compared in the included studies were umifenovir (Arbidol) [25,29,31,47], baloxavir marboxil [30], enisamium [50], SARs-CoV-2 OR SARs OR COVID-19 OR "coronavirus" OR covid AND ("antiviral drugs") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial") PubMed 12-04-2021 14…”

“…One study was originally included, but was later retracted due to concerns about data integrity, and thus was excluded [ 42 ]. Antiviral treatments compared in the included studies were umifenovir (Arbidol) [ 25 , 29 , 31 , 47 ], baloxavir marboxil [ 30 ], enisamium [ 50 ], favipiravir [ 25 , 30 , 35 , 40 – 42 , 44 , 45 , 48 , 52 ], lopinavir/ritonavir (LPV/r) [ 24 , 26 , 27 , 29 , 31 , 37 , 38 , 44 , 47 ], remdesivir [ 23 , 34 , 36 , 39 , 51 , 53 ], ribavirin [ 22 ], sofosbuvir/daclatasvir [ 22 , 32 , 33 , 46 , 49 ], sofosbuvir/ledipasvir [ 28 ], sofosbuvir/ravidasvir [ 46 ], and sofosbuvir/velpatasvir [ 43 ]. The study characteristics and baseline patient characteristics are summarized in Table 2 .…”

“…One study evaluated the efficacy of enisamium, an antiviral drug whose metabolite is a viral RNA polymerase inhibitor [ 98 ]. Holubovska et al conducted a double-blind, placebo-controlled, phase 3 trial comparing enisamium to a placebo [ 50 ]. No differences in time to recovery was found overall or among patients who did not initially require oxygen.…”

Coronaviral Infection and Interferon Response: The Virus-Host Arms Race and COVID-19

“…Even those drugs with weak pharmaceutical activity toward SARS-CoV-2 work well at the early stages of infection when multiplication of viruses occurs. For example, Enisamium iodide, an isonicotinic acid derivative, which was reported as an inhibitor of RdRp of influenza A and B virus strains, recently was suggested to have the potential to prevent severe development of COVID-19 by inhibiting RNA synthesis of SARS-CoV-2 [ 148 , 149 , 150 , 151 , 152 ]. Moreover, Enisamium can directly inhibit influenza and SARS-CoV2 RNA replication, and recent clinical trials showed that COVID-19 patients recover faster and safer when prescribed with Enisamium compared to the placebo group [ 152 ].…”

“…For example, Enisamium iodide, an isonicotinic acid derivative, which was reported as an inhibitor of RdRp of influenza A and B virus strains, recently was suggested to have the potential to prevent severe development of COVID-19 by inhibiting RNA synthesis of SARS-CoV-2 [ 148 , 149 , 150 , 151 , 152 ]. Moreover, Enisamium can directly inhibit influenza and SARS-CoV2 RNA replication, and recent clinical trials showed that COVID-19 patients recover faster and safer when prescribed with Enisamium compared to the placebo group [ 152 ]. Meantime, the popular antiviral composition Lopinavir/Ritonavir (HIV 3CLpro inhibitors) and other HIV protease inhibitors did not reveal any efficacy to improve the outcomes of COVID-19 patients based on multiple studies [ 153 , 154 , 155 ].…”