Remdesivir therapy for COVID-19

Introduction  

COVID-19 infection presents with varying severity, ranging from asymptomatic carriage to mild respiratory tract infection and severe or fatal pneumonia. The condition has turned out to be a public health emergency of international concern (PHEIC), declared by the World Health Organization (WHO).¹

Though most infections of COVID-19 are selflimited, about 15% of infected persons develop severe pneumonia necessitating administration of supplemental oxygen and another 5% progress to critical illness with hypoxemic respiratory failure, acute respiratory distress syndrome and multiorgan failure requiring ventilatory support, and nearly half of them succumb to the disease². World is looking forward for a specific antiviral drug with proven efficacy for treatment of patients with severe coronavirus disease 2019 (COVID-19).

There is no approved therapy for the Covid-19, which can cause severe pneumonia and acute respiratory distress syndrome in some patients. Trials of several drugs are in progress. Among them remdesivir has elicited great interest and hope for the treatment³. Back in February, the World Health Organization said remdesivir showed potential against Covid-19. The current pandemic of COVID-19 is in need for an effective antiviral agent against SARS-CoV-2. Remdesivir may be used as a therapy for patients with COVID-19. It is undergoing clinical trials worldwide.

Broad-spectrum antiviral activity

Remdesivir (developmental code, GS 5734) is a broad-spectrum, small molecule antiviral agent, developed by Gilead Sciences, a biopharmaceutical company based at Foster City, Calif, USA, as a treatment for Ebola virus infection⁴. The team was led by Czech Scientist Tomas Cihler, a specialist in Virology.

It is a monophosphoramidate prodrug of an adenosine C-nucleoside exhibiting a broadspectrum antiviral activity on filoviruses, paramyxoviruses, pneumo-viruses, and coronaviruses⁵. Remdesivir gets metabolised into its active form that obscures viral RNA polymerase and evades proofreading by viral exonuclease, resulting in a decrease in viral RNA production⁴.

Remdesivir has shown antiviral activity against many variants of Ebola virus in cell-based assays and in a rhesus monkey model of Ebola virus disease^5,6.

In vitro studies carried out on Remdesivir have shown that it can inhibit replication of many RNA virus families such as Coronaviridae (SARS-CoV, MERS-CoV), Paramyxoviridae (Nipah virus, respiratory syncytial virus and Hendra virus), and Filoviridae (Ebola virus)⁷.

Being a nucleoside analogue, remdesivir acts as an inhibitor of RNA-dependent RNA polymerase (RdRp), targeting the viral genome replication process.  The RdRp is the protein complex which CoVs utilise to replicate their RNA-based genomes. Following metabolization, remdesivir is converted into active nucleoside triphosphate (NTP) in many human cell lines, and the metabolite competes with natural nucleotide, adenosine triphosphate (ATP) for incorporation into the nascent RNA strand (8). It implies that any drug targeting RNA-dependent RNA polymerase (RdRp) proteins of SARS CoV is likely to be effective for SARS CoV-2.

It results in premature termination of RNA synthesis. The growth of the RNA strand gets halted. Remdesivir is likely to outpace viral proofreading process that is able to detect and remove other nucleoside analogues and maintains its antiviral activity⁹.

In vitro studies

Most of the in vitro studies carried out on Vero E6 cell line, till now have shown positive results on the anti-CoV activity of remdesivir. In an in vitro efficacy study, Wang and colleagues examined the effect of remdesivir against SARS CoV-2 using Vero E6 cell lines (originated from African green monkey kidney epithelial cells) and found it to possess low potency for inhibiting SARS-Cov-2. The mechanism for remdesivir involved the host cells’ post-entry stage¹⁰. Remdesivir is a potent inhibitor of replication of SARS-CoV-2 in human nasal and bronchial airway epithelial cells¹¹.

Clinical trials

Remdesivir was used on compassionate grounds on a patient who presented with COVID-19 pneumonia in January 2020 in the US for the first time. This 35-year old male patient had acquired the infection during travel to Wuhan. He was given intravenous remdesivir on the seventh day of hospitalization and showed improving signs the next day. There were no adverse events related to the use of remdesivir¹².

There are many anecdotal reports following this. 17 passengers on the Diamond Princes cruise ship who developed severe infection due to COVID-19 were treated with intravenous remdesivir for 10 days and the patients became less dependent on ventilatory support⁷.

The Food and Drug Administration of the US approved an emergency use authorization for the drug that will allow it to be prescribed for hospitalized patients infected with the coronavirus.

Evaluation of the efficacy and safety of remdesivir has been done through another randomised, controlled, double-blind clinical trial on 308 hospitalised patients with mild-to-moderate COVID-19 respiratory illness in Jin Yin-tan hospital, Capital Medical University, Wuhan, Hubei, China. They were randomised to either remdesivir or placebo arms. Remdesivir was administered as 200 mg loading dose on day 1 followed by 100 mg daily for 9 days. The drug was given as an intravenous infusion. The primary outcome was defined as the time to make clinical recovery up to 28 days, as defined by normalization of body temperature, respiratory rate, and oxygen saturation, and the resolution of cough for at least 72 h¹³. The trial was suspended. There were no significant reductions in viral load.

The most common adverse effects in studies of remdesivir for COVID-19 include respiratory failure, hyp albuminaemia, hypokalaemia, anaemia, thrombocytopaenia, and yellowish discolouration of skin¹⁴.   Other reported side effects include gastrointestinal distress, elevated transaminases, and infusion site reactions.

In a randomised, double-blind, placebo-controlled, multicentre trial at 10 hospitals in Hubei, China, Wang and colleagues took adults admitted to hospital, with laboratory-confirmed SARS-CoV-2 infection with an interval from hospital with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mg Hg or less, and radiologically confirmed pneumonia¹⁵. The patients were randomly assigned in a 2:1 ratio to remdesivir, who received 200 mg of the drug as intravenous infusion on the first day followed by 100 mg on subsequent 9 days, or the same volume of placebo infusions for 10 days. The patients received lopinavir-ritonavir, interferons and corticosteroids concomitantly.

237 patients were enrolled and randomly assigned to treatment group (158 to remdesivir and 79 to placebo). The results showed that patients with symptom duration of 10 days or less receiving remdesivir exhibited faster clinical improvement compared to those on placebo. However, the results were not statistically significant. Adverse events were noted in 102 (66%) of 155 redemsivir recipients vs 50(64%) of placebo recipients. Remdesivir had to be stopped early in 18(12%) patients due to adverse events vs four (5%) in placebo early.

In a randomised, double-blind, controlled trial (Adaptive COVID-19 Treatment Trial (ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) in the US.

The adults hospitalised with COVID-19 showing infection in the lower respiratory tract and moderate-to-severe disease requiring supplemental oxygen, found a 10-day course of remdesivir to be superior to placebo in the treatment of patients with COVID-19¹⁶. The study was carried out on 1,063 participants in 60 trial sites spread over the US, Mexico, Greece, Germany, Singapore, Japan and Korea. The patients were randomly assigned to receive a 10-day course of remdesivir intravenously(n=538) or a placebo(n=521) along with local standard care. The preliminary analysis has shown that those who received remdesivir had a shorter time to recovery (being discharged from the hospital or being medically stable enough go be discharged from the hospital) than those who received placebo. The median time was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. The clinical status between the study groups on day 15, it was found that the odds of improvement in the ordinal scale were higher in the remdesivir arm than in the placebo arm of the trial. There was a survival benefit, with a 14-day mortality rate of 7% for the group receiving remdesivir compared to nearly 12% for the placebo group. The difference in mortality was not significant.

Remdesivir was administered on a compassionate -use basis to 61 patients hospitalised in the US, Canada, Europe and Japan with Covid-19 who had an oxygen saturation of 94% or less while breathing room air or receiving oxygen support. They received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. during January 2020 through March 2020. The data of 53 patients was analysed¹⁷. At baseline 30 patients (57%) were receiving mechanical ventilation and 4 (8%) extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including¹⁷ of 30 patients receiving mechanical ventilation who were extubated. A total of 25(47%) patients were discharged and 7(13%) patients died due to multi-system organ failure. A clinical improvement was seen in 36 of 53 (68%) patients. Older patients and those with pre-existing respiratory or cardiovascular conditions appear to be at the greatest risk for severe complications.

In a trial sponsored by the National Institute of Allergy and Infectious Diseases 1,063 patients with COVID-19 were given remdesivir or a placebo. The time to recovery averaged 11 days among those who got the drug, compared with 15 days for those who got the placebo.  Remdesivir reduced the time to recovery for surviving patients from 15 days to 11 days, a 31% improvement. Anthony Fauci was optimistic that remdesivir would become ‘the standard of care’ for patients with Covid-19¹⁴.

Remdesivir is an RNA polymerase inhibitor with potent antiviral activity. In a randomized, open label, phase 3 trial on hospitalized patients from 55 hospitals in the US, European and SouthEast Asian countries, with COVID-19 infection, exhibiting oxygen saturation of 94% or less while breathing on room air or receiving supplemental oxygen, and radiological evidence of pulmonary infiltrates¹⁸.  Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received intravenous remedsivir for either 5 days or 10 days. Remdesivir was given in a dose of 200 mg on first day to be followed by 100 mg daily subsequent 4 days or 9 days.

There were 200 patients in 5-day administration and 197 in 10-day administration (total 397 patients). The clinical status was more severe in the group that received treatment for 10 days. The most common adverse events noticed were nausea, worsening of respiratory failure, and elevated alanine amino-transferase and constipation.  The study did not reveal any significant different difference between 5-day course and a 10-day course of remdesivir.

The first randomised trial of remdesivir in patients with severe COVID-19 carried out in China by Wang and co-workers, has not shown a statistically significant treatment benefit from remdesivir treatment. The study sought a treatment effect of hazard ratio (HR) 1·40, translating to reducing median time to clinical improvement to 15 days (remdesivir) vs 21 days (placebo). The observed HR of 1.23 suggests that a benefit, if it exists, might be smaller than anticipated¹⁹. 22 (14%) of 158 patients on remdesivir died vs ten (13%) of 78 on placebo, and there was no signal that viral load decreased differentially over time between remdesivir and placebo groups.

The clinical trial carried out by National Institute of Allergy and Infectious Disease (NSAID) part of National Institute of Health (NIH), US since February 2020, on hospitalised patients with advanced COVID-19 and lung involvement who received daily infusion of remdesivir for 10 days, recovered faster than similar patients who received placebo. The interim analysis from a randomized, controlled trial involving 1063 patients (Adaptive COVID-19 Treatment Trial, or ACTT) carried out in the US to evaluate an experimental treatment for COVID-19 has shown promising results (20). The primary end point was the time to recovery that is defined as being well enough for hospital discharge or returning to normal activity level. NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19.

Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. The study has concluded that remdesivir is superior to the standard care given to COVID-19 patients. However, there is a note of caution that remdesivir alone is not likely to be sufficient.

ClinicalTrials.gov indicates that five randomised trials involving remdesivir are recruiting globally, with one in severe COVID-19 from Gilead (NCT04292899), the drug manufacturer, with a target of 6000 participants; naively, this trial should be adequately powered.

Pooling of data from many high-quality studies will definitely a good insight into its effectiveness on different stages of disease and its safety. It is hoped the ongoing trials in different parts of the world will provide useful information.

Gilead Sciences, Inc initiated two randomized, open-label, multi-centre Phase-3 clinical trials for remdesivir The first SIMPLE trial evaluated the safety and efficacy of 5-day and 10-day dosing regimens of remdesivir in hospitalized patients with severe manifestations of COVID-19. The initial phase of the study randomized 397 patients in a 1:1 ratio to receive remdesivir 200 mg on the first day, followed by remdesivir 100 mg each day until day 5 or 10, administered intravenously, in addition to standard of care²¹.

The study has shown that the time to clinical improvement for 50 percent of patients was 10 days in the 5-day treatment group and 11 days in the 10day treatment group. More than 50% of patients in both treatment groups were discharged from the hospital by day 14 (5-day: 60.0%, n=120/200 vs.10-day: 52.3% n=103/197; p=0.14). At Day 14, 64.5 percent (n=129/200) of patients in the 5-day treatment group and 53.8 percent (n=106/197) of patients in the 10-day treatment group achieved clinical recovery. The overall mortality rate at Day 14 was 7 percent (n=23/320) across both treatment groups.

In an exploratory analysis of the study, it was found the patients who received remdesivir within 10 days of symptom onset had improved outcomes compared with those treated after more than 10 days of symptoms. The pooled data across treatment arms, by Day 14, 62 percent of patients treated early were able to be discharged from the hospital, compared with 49 percent of patients who were treated late.

The results have indicated that patients who received a shorter, 5-day course of remdesivir experienced similar clinical improvement as patients who received a 10-day treatment course. The adverse events noted during treatment were nausea, acute respiratory failure, and elevated levels of liver enzymes.

An expansion phase second SIMPLE trial has been added recently and will enrol an additional 5,600 patients, including patients on mechanical ventilation. The study is being conducted at 180 trial sites around the world, including sites in the United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, the Netherlands, Singapore, Spain, Sweden, Switzerland, Taiwan, India and the United Kingdom. This study is evaluating the safety and efficacy of 5-day and 10day dosing durations of remdesivir administered intravenously.