Remdesivir developed by an American biopharmaceutical company is a broad spectrum antiviral medication. Lab tests by Gilead Sciences suggested Remdesivir was active against severe acute respiratory syndrome ( SARS ) & Middle east respiratory syndrome ( MERS ) in animal models, both of which is caused by Corona virus. It has become clear that COVID-19 is also caused by a Corona virus ( SARS-CoV-2 ) and hence laboratory testing of Remdesivir began in January 2020.
Production of Remdesivir involves long, linear chemical synthesis process. This includes several specialized manufacturing steps & novel substances which must be completed sequentially. The process takes weeks to complete
Remdesivir as investigative treatment
Outbreak of the COVID-19 viral pandemic got the researchers to try out available options since developing a vaccine to fight the pandemic would take over a year.
The World Health Organization ( WHO ) announced on 18 March 2020 the launch of Solidarity clinical trail for COVID-19, which would include 1 group treated with Remdesivir. “Solidarity trail” enrolls patient from multiple countries & is aimed to discover the effect of the drug used in reducing disease progression or improving survival.
Adaptive COVID-19 treatment trail ( ACTT ) was done on February 21, 2020 for 1063 patients by the US based National Institute of Allergy and Infectious diseases ( NIAID ). ACTT was designed to incorporate investigative treatments as pandemic progresses.
Gilead Sciences the maker of Remdesivir is conducting two randomized clinical studies in a compassionate use program for adults diagnosed with COVID-19. The study evaluates the safety and efficacy of Remdesivir for 2 dosing durations of 5 days & 10 days.
How Remdesivir blocks the Corona virus
Viruses have their own genetic code but they don’t have the machinery to copy their DNA. Viruses use the keys on its surface to gain entry into host cells & use their machinery to reproduce themselves. The Coronavirus have spike like proteins called S proteins on it’s surface. The surface of the human cell have a lot of proteins one of which is Angiotensin Converting Enzyme – 2 or ( ACE2 ). The ACE2 interacts with the S protein leading to the entry of the virus into the host cell. SARS-CoV-2 has no viral envelope and enters the host cell through endocytosis, which means the virus knocking at the door of the cell tricks the cell into believing it is nutrition. Once inside, the virus hijacks the host cell. The S protein & other surface proteins of the virus cell are degraded in the cytoplasm of the host cell. The genetic encoding of the SARS 2 Coronavirus is a single stranded RNA and are the longest known viral RNA genome. The viral RNA are now released which spreads out to replicate.
The coronavirus RNA genome hijacks the ribosome of the host cell and does it easily as it has a 5’ methylated cap and 3’ poly A tail. The viral RNA uses the ribosome to generate an enzyme called Polymerase enzyme.
Polymerase enzyme synthesis the nucleotide components that make the RNA strand. Remdesivir targets the Polymerase enzyme. Remdesivir appears to the Polymerase as adenine, one of the nucleotides and attaches to the chain. Once Remdesivir is attached to the chain the nucleotides can no longer attach to it and hence the chain is broken.
Remdesivir in treatment of COVID-19
Anthony Fauci recognized as one of the world’s leading experts on infectious diseases & who is the director since 1984 of National Institute of Allergy and Infectious diseases ( NIAID ) announced on 30th April 2020 that a Randomized double blind placebo control (RDBPC) study considered the “gold standard” of epidemiologic studies was conducted using Remdesivir
68 sites were involved in this RDBPC. This included 47 in the US & 21 countries in Europe and Asia. RDBPC is where, one section of patients is given a Placebo & the other Remdesivir; the medical staff giving the treatment is also not aware of this differentiation like the patients, hence the term double blind. There is an independent data & safety monitoring which has all the information to monitor the progress. Patients treated with Remdesivir had a faster recovery time of 11 days compared with 15 days for the Placebo controlled group. The mortality rate was also better with 8.0 % for the section treated with Remdesivir compared to 11.6 % for those given Placebo
Compassionate Use Program by Gilead Sciences
Gilead Sciences on April 10 announced the analysis results of patients who had severe complications of COVID-19 & were treated with investigational antiviral Remdesivir between January 25, 2020 through March 7, 2020 under the Compassionate Use Program. There were 53 patients for the analysis who were hospitalized with ( SARS-CoV-2 )severe acute respiratory coronavirus infection and an Oxygen saturation of 94 % or less who had fairly healthy levels of kidney & liver functions. They had to agree not to use any other antiretrovirals which are under investigational use. They received at least 1 dose of Remdesivir on or before March 7, 2020 and were not just from the US but included patients from Europe, Canada & Japan. The treatment included a 10 day course of Remdesivir administered intravenously. The loading dose on day 1 was 200 mg followed by 100 mg daily for the remaining 9 days.
The figure explains the status of patients. 7 patients died out of which 6 were from the invasive group & 1 from the Noninvasive group. Out of 34 patients in the invasive group 19 improved; 3 to the Noninvasive group, 8 to Ambient air and 8 were discharged. Of the 7 in the invasive group 5 were discharged & 1 remained in treatment. The low-flow oxygen had 10 patients all were discharged, Ambient air had 2 patients both discharged.
Remdesivir 5 day trail
Gilead also conducted a study with a 5 day dosage of Remdesivir, It included a first day dose of 200 mg and 100 mg dose for the next 4 days. Atleast 50%of the patients improved and were discharged from the hospital in 2 weeks. The study shows that some people could be treated with a 5 day regimen. It is optimizing the current supply of Remdesivir and helping Hospitals to attend more patients in urgent need of medical treatment
Side effects of Remdesivir
Infusion-Related reactions; Signs & symptoms include Low blood pressure, nausea, vomiting, shivering and sweating. Increase in level of Liver enzymes, Rashes and or yellow discoloration of the skin
Approval of Remdesivir to treat patients with COVID-19
The US Food and Drug administration ( FDA ) on May 1, 2020 approved temporarily the emergency use of Remdesivir in hospitalised patients with severe COVID-19.
The Committee for Medicinal Products for Human Use ( CHMP ) which plays a vital role in authorization of medicines in the European Union has recommended the compassionate use of Remdesivir. The recommendations have been updated based on the preliminary results of the ACTT study by National Institute of Allergy and Infectious diseases ( NIAID ). Remdesivir has also been granted regulatory approval by the Japanese Ministry of health, Labour & welfare as a treatment for SRS-CoV-2.