All you wanted to know about Remdesivir

Remdesivir is an antiviral drug. It was originally developed by the US-based biopharmaceutical firm Gilead Sciences to fight the Ebola outbreak in Africa in the year 2010.

Remdesivir is a nucleoside analogue drug. Nucleoside analogues are a class of antiviral drugs that are currently used for the treatment of HIV, herpes simplex virus infection, cytomegalovirus infection and hepatitis B.

Nucleosides are the building blocks of DNA and RNA. They are made of sugar (ribose sugar for RNA and deoxyribose sugar for DNA) and a nitrogenous base (a nitrogen-containing compound). There are four types of nitrogenous bases that are arranged in various orders to make DNA and RNA chains. These bases include - Adenine [A], Guanosine [G], Cytosine [C] and Thymine [T]. In RNA, Uracil [U] is present in place of Thymine.

To be able to make a chain, these nucleosides bind with three phosphate groups and get converted into nucleotides - Adenosine triphosphate (ATP), GTP, CTP, UTP and TTP. These nucleotides then connect to each other through the phosphate group to form the sugar-phosphate backbone of DNA or RNA.

Knowing this structure is important to understand how the drug works: Remdesivir goes and replaces an important part of the viral RNA: the ATP. This action is supposed to affect the virus' ability to make more copies of itself (replicate). When the virus is no longer able to multiply in the host's body (in this case, the COVID-19 patient), the infection eventually goes away.

However, this is not a simple procedure. The virus has a proofreading mechanism - meaning, it can tell when there's a change (mistake) in its structure and fix that mistake. So far, scientists say, the COVID-19 virus has not been able to fix the mistake introduced by Remdesivir.

Remdesivir is actually a prodrug of the adenosine analogue GS-441524. This means the drug needs to be metabolised in the body to become active. Once, inside healthy cells, Remdesivir is converted into its active nucleotide triphosphate (NTP) form. 

Once it gets activated, Remdesivir then inhibits the functions of RNA polymerase, the enzyme that RNA viruses like SARS-CoV-2 use for replicating (making copies of) their genetic material.

Being an Adenosine analogue (look-alike), Remdesivir competes with ATP for integration into the viral RNA. As the drug gets integrated into the viral RNA, it causes replication to stop completely after the addition of a few more nucleotides. 

Interestingly, even though coronaviruses have a proofreading mechanism in their RNA polymerase (something that most other RNA viruses lack), studies show that this mechanism cannot find the fault in the replication process created by Remdesivir. However, experts are concerned about a possible mutant of the virus that may be able to find out this error and may then have resistance to Remdesivir.

Read more: What is passive antibody therapy for COVID-19? 

Remdesivir is still under investigations to study its efficacy and side effects (if any). 

In vitro (lab) and in vivo (animal) studies show that Remdesivir is effective against SARS-CoV the causative agent of SARS (Severe Acute Respiratory Syndrome) and MERS-CoV, the causative agent of MERS (Middle Eastern Respiratory Syndrome).

At least four different Phase 3 trials are underway (or are almost done) to test the effect of Remdesivir on COVID-19 patients. Phase 3 clinical trials involve re-testing the findings of the earlier trials, with more than 1,000 patients, to study the safety and efficacy of a drug. 

Three of these trials are being funded by US-based agencies - one by the NIH's National Institute of Allergy and Infectious Diseases (NIAID), and two at Gilead Sciences. The fourth one is being conducted at INSERM (Institut National de la Santé et de la Recherche Médicale) in France.

The National Institute of Health (NIH) started conducting clinical trials on Remdesivir in late February. The study, which includes more than 1,000 patients, spread across 68 sites in the USA, Europe and Asia, was till then the biggest study on Remdesivir. Findings from the trial (mentioned in an April 29 news release by the NIH) indicated that:

• Remdesivir is more effective than placebo for improving lung function in COVID-19 patients.
• Preliminary data from the study showed that about 31% patients who received Remdesivir recovered more quickly than those who got a placebo.
• The mortality rate in Remdesivir group was 8% in comparison to the 11.6% in the placebo group, according to the release.
• Patients who got treated with Remdesivir were able to leave the hospital in 11 days in comparison to the placebo group who took 15 days to get discharged.

Out of the two Gilead trials initiated in March, one is for severe COVID-19 while the other is for moderate COVID-19. Between the two trials, the drug will be tested on more than 7,500 people.

The trials are still underway, as per the registry of clinical trials by NIH. However, Gilead has released (on its website) the results from the trials so far. As per the news release, the results show that:

• With a five-day or 10-day treatment plan with Remdesivir, patients showed clinical improvement by Day 10 and Day 11, respectively.
• More than 50% of patients were able to leave the hospital by Day 14.  

Two other trials that began in China as early as February 2020 to study the effect of Remdesivir on mild, moderate and serious cases of COVID-19 were terminated due to lack of patients.

Read more: Ebola drug Remdesivir enters human trials for COVID-19

A recent study published in The Lancet showed the findings of a Remdesivir study done across various hospitals in China. As per the article, 237 patients were given Remdesivir versus a placebo intravenously in a 2:1 ratio. The first dose was 200 mg and after that, a 100 mg intravenous infusion was given from Day 2 to Day 10 once a day. Although the Remdesivir group noted faster improvement in symptoms in the patients who started treatment earlier, the drug did not seem to have any statistically significant effects on the treatment.

However, it is important to note that the Remdesivir group had more patients with heart conditions. Diabetes, heart diseases and hypertension were the most common comorbidity in all patients.

Clinical trials proposed a dosage of 200 mg on Day one followed by 100 mg once daily intravenously for up to nine days. However, the exact dosage to be administered is still unknown.

The FDA has also approved only intravenous administration of Remdesivir. Under the emergency use authorization, the FDA has suggested that patients should be given a 10-day Remdesivir treatment if they are on ECMO or mechanical ventilation. However, for those who do not require such invasive ventilation procedures, they are suggested to be given only a five-day Remdesivir treatment.

Read more: Coronavirus vaccine candidates

Side effects of Remdesivir are not completely known. Though the FDA has listed two possible side effects of this drug:

• Liver injury: Liver injury is a common side effect of most nucleoside analogues. In the Gilead trials, about 7.3% of patients observed increased levels of liver enzymes - an indicator of liver injury. Before giving Remdesivir to a patient, doctors check the liver function of the patient. Read more: Liver function test
• Infusion-related reaction: Remdesivir is to be given intravenously only as per the FDA recommendations. Infusion reaction is the body’s hypersensitive reaction against the administration of a drug. Patients with infusion-related reactions show side effects like shivering, sweating, nausea and vomiting and low blood pressure. In the Gilead trial, around 10% people had nausea. 
• Reactions related to venous administration of the drug (through injections) can also show up, these include bruising, mild pain, bleeding and soreness and possible infection at the site of needle insertion.

Read more: What is fluid therapy?

There isn’t enough evidence to say anything about the safety of Remdesivir in pregnancy. According to the US FDA, the benefits of Remdesivir may outweigh its side effects for pregnant and breastfeeding women. Still, pregnant women are suggested to go with their doctor’s suggestions.

Read more: Pregnancy and labour management of women with COVID-19 infection

There isn’t enough data to say anything for sure about the effects of Remdesivir on patients with chronic diseases.

Read more: COVID-19 prevention tips for old people and those with chronic diseases

In animal models, Remdesivir has shown some prophylactic (preventive) benefits against MERS virus. Administration of the drug 24 hours prior to exposure to the virus completely prevented that disease. Lab studies show that Remdesivir can completely inhibit SARS-CoV-2, the causative agent of COVID-19. However, no clinical studies are currently available to support the evidence.

Remdesivir is still under investigations and not even an approved drug as per the FDA. It is only approved right now to treat severe cases of COVID-19.

Gilead Sciences reportedly owns the patent for Remdesivir in India right now. The patent was given to the biopharmaceutical company in February 2020 and will not expire before 2035. However, as per media reports, Gilead may announce licence agreements with various pharma companies in India, allowing them to develop a more generic and cost-effective version of the drug in the country.

Companies including Cipla and Glenmark have reportedly already started developing the raw materials (APIs) for Remdesivir locally. This would help them to quickly manufacture multiple doses of the drug when they get the licence.

A drug licence allows a company to make, sell and use a drug that has been patented by another organisation.

Remdesivir is quite similar to another drug Favipiravir that is being considered as a strong candidate for COVID-19 treatment. Favipiravir is another nucleoside analogue - except, it competes with both A and G (which are together called purines, the other two C and T or U are called pyrimidine) nitrogen bases rather than ATP. Unlike Remdesivir that stops the viral RNA replication, Favipiravir causes mutations in the RNA leading to significantly reduced viral load.

Favipiravir was originally licensed in Japan to treat influenza and has since been used successfully to treat Ebola patients. Studies indicate that it is hard for viruses to develop resistance to this drug. Favipiravir is contraindicated in pregnant women, as it can negatively affect the foetus.

Hydroxychloroquine is another drug that has got considerable public attention in the previous months. Originally used to treat malaria, the drug falls under the category of disease-modifying anti-rheumatic drugs and is hence given to treat rheumatoid arthritis. Additionally, Hydroxychloroquine is used to treat lupus.

Hydroxychloroquine interferes with the process of inflammation and cytokine production in the body when it is fighting an infection. Inflammation and overproduction of cytokines are what cause lung damage and other symptoms in COVID-19 - in some cases, they may lead to death.

Hydroxychloroquine is currently being recommended as a prophylactic drug against COVID-19 for specific groups of people, like medicos. However, this medicine has some side effects, and should never be taken without a doctor's prescription.

India is the leading producer of hydroxychloroquine in the world. So far, there is no clear evidence on the effect of this drug in COVID-19. Two studies done in China and France suggest that this drug may be effective in treating COVID-19 patients, while another study done in France says that it can’t. An observational study done by the Indian Council of Medical Research (ICMR) has indicated possible side effects like nausea, abdominal pain and low blood pressure with regular use. Hydroxychloroquine has several potential side effects also, which include minor effects like nausea and vomiting, diarrhoea, and abdominal cramps and severe effects like cardiomyopathy and kidney damage.

Another drug combo lopinavir-ritonavir that is being considered for COVID-19 treatment does not have strong evidence to back it yet. Originally used for the treatment and prevention of HIV, this drug combo was approved by the ICMR for the treatment of COVID-19 in India after two people recovered from the disease after being given the drugs.

However, various studies done in China have shown that the drug has no significant action.