Remdesivir

Remdesivir, also known as GS-7734, is a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-441524). Remdesivir is a drug candidate developed in 2017 by Gilead Sciences, in collaboration with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), University of California – San Diego and the Centers for Disease Control and Prevention (CDC). The drug was originally developed for treatment of Ebola infection, but in clinical trials it was found to be less effective than other treatments. Remdesivir has potential to treat coronavirus 2019-nCoV. Novel coronavirus (2019-nCoV) is closely related to severe acute respiratory syndrome Coronavirus (SARS-CoV).

Remdesivir is a Nuc inhibitor. Nuc inhibitors are nucleotide or nucleoside analogs that are incorporated into viral RNA or DNA in place of the nucleoside that is supposed to be there. Nuc inhibitors inhibit viral replication. They function as chain terminators, preventing the elongation of the RNA or DNA by constraining the conformation or hindering linkage with an incoming nucleotide. Remdesivir is a monophosphoramidate prodrug, of the C-adenosine nucleoside analogue GS-441524. Remdesivir metabolizes to form an adenosine analog with potent activity against the Filoviridae, Paramyxoviridae, Pneumoviridae and Orthocoronavirinae RNA virus families. Remdesivir targets the viral RNA dependent RNA polymerase (RdRp).

Remdesivir (GS-5734) is a prodrug that is converted into the C-adenosine nucleoside analog GS-441524 (A).

SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Previously SARS-CoV-2 was known as novel coronavirus (2019-nCoV), a previously unknown pathogen, causing pneumonia and related to SARS-CoV, that emerged in Wuhan, China in December, 2019. Chinese authorities reported 2835 cases in mainland China and 81 deaths and numerous other countries had confirmed cases of 2019-nCoV. Assessment of remdesivir by controlled trial is planned in partnership between Gilead Sciences and the Chinese health authorities. A placebo-controlled Phase II trial of remdesivir is planned at Friendship Hospital in Beijjing, China and has been set to enrol 270 patients with mild and moderate pneumonia caused by 2019-nCoV. In the absence of any approved treatment options, Gilead has offered remdesivir to a small number of patients with 2019-nCoV as emergency treatment. Remdesivir was given to the first American confirmed to be infected with 2019-nCoV. In 2020, Gilead announced partnerships with NIAID, the FDA, the U.S. Centers for Disease Control and Prevention (CDC), the U.S. Department of Health and Human Services (HHS), the China CDC and National Medical Product Administration (NMPA), the World Health Organizatioin (WHO) and individual researchers and clinicians to help patients and communities fighting 2019-nCoV.

A February, 2020 report found that in human cultured cells infected with 2019-nCoV, remdesivir were found to be effective at controlling infection. Clinical trials for Remdesivir were initiated in partnership between Gilead Sciences and the China-Japan Friendship Hospital in Beijing and by the NIH in the U.S. Gilead has plans to begin two phase III clinical studies in Asian countries in March, 2020 to assess dosing for intravenous administration of remdesivir. The U.S. FDA accepted the investigational new drug (IND).

On April 29, 2020, NIAID released preliminary data from their study showing that patients that received remdesivir recovered faster (11 days) than patients that received placebo (15 days). Also on April 29, 2020, Gilead released data from their clinical study which showed that a five-day course and ten-day course of remdesivir showed similar rates of clinical improvement. The Gilead study did not include placebo controls. On the same day a study based in China was published in the Lancet which found that remdesivir did not significantly improve time to clinical improvement, mortality or time of clearance of virus compared with placebo. The China study enrolled more severe cases of COVID-19 than the NIAID study and had not been able to enroll as many patients as planned because of the decrease in cases in Wuhan.

Gilead reported that remdesivir showed in vitro and in vivo activity in animal models against MERS and SARS, which are coronaviruses with similar structure to 2019-nCoV. Remdesivir reduced virus titer in mice infected with Middle East Respiratory Syndrome Coronovirus (Mers)-CoV, improved lung tissue damage with effects better than in mice treated with Lopinavir/Ritonavir combined with interferon-beta. Remdesivir was shown to have antiviral activity against endemic human COVs, OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC₅₀ values. The drug was also shown to be efficacious against porcine deltacoronavirus (PDCoV).

Therapeutic efficacy of remdesivir was shown in non-human primates against Ebola virus. Remdesivir was one of the experimental Ebola treatments removed from the Pamoja Tulinde Maisha clinical trial. According to the NIH, Remdesivir and the other drug, ZMApp, were less effective at preventing death than the other two drugs studied which were mAb114 an REGN-EB3.