India has revised the protocol for clinical management of Covid-19 to include the use of Remdesivir and off-label use (the use of a prescription drug for a condition other than what it has been officially approved for) of tocilizumab and convalescent plasma therapy on specific groups of patients the Indian Express reports.
According to the article, the list of symptoms has been revised in the new protocol to include the loss of smell and taste.
Remdesivir is an antiviral that was originally developed in 2014 by the California based biopharma company Gilead Sciences for the treatment of Ebola. The Drugs Controller General of India has on June 1, 2020, approved its treatment for suspected or laboratory-confirmed cases of Covid-19 in adults and children hospitalized “with severe disease”. The drug is part of the World Health Organisation’s ongoing Solidarity Trials, and it received emergency use authorization by the United States Food and Drug Administration (USFDA) on May 1.
Tocilizumab is an immunosuppressant that is commonly used as a treatment for rheumatoid arthritis. It is manufactured by Roche Pharma and marketed by Cipla; in India, the drug is sold under the brand name Actemra. Tocilizumab has already been tried on some seriously ill patients in Mumbai. Convalescent plasma therapy or CPT involves the transfusion of the blood plasma of a recovered patient into another patient. The procedure has been used for several diseases earlier, but its efficacy for Covid-19 is still under investigation. But oxygenation is still an important part of the treatment protocol which says that the median incubation period of the virus is 5.1 days, with a range of 2-14 days. “The precise interval during which an individual with Covid-19 is infectious is uncertain. As per the current evidence, the period of infectivity starts two days prior to the onset of symptoms and lasts up to eight days. The extent and role played by pre-clinical/ asymptomatic infections in transmission still remain under investigation,” the protocol says.
On Remdesivir, tocilizumab, and CPT, which appear in the section on investigational therapies, the document says: “Remdesivir (under Emergency Use Authorization) may be considered in patients with moderate disease (those on oxygen)… Tocilizumab (Off Label) may be considered in patients with moderate disease with progressively increasing oxygen requirements and in mechanically ventilated patients not improving despite the use of steroids. Long term safety data in Covid-19 remains largely unknown… Convalescent plasma (Off Label) may be considered in patients with moderate disease who are not improving (oxygen requirement is progressively increasing) despite the use of steroids.”
There are of course precautions to be taken and there are contra-indications Remdesivir, for example, is not to be used in cases of severe renal impairment, in children below the age of 12 years, and in pregnant or lactating mothers. Tocilizumab should be used only after existing infections have been checked for, and tuberculosis has been ruled out.
On HCQ, the document says: “This drug has demonstrated in vitro activity against SARS-CoV-2 and was shown to be clinically beneficial in several small single-center studies though with significant limitations. Nonetheless, several large observational studies with severe methodologic limitations have shown no effect on mortality or other clinically meaningful outcomes. As such, the evidence base behind its use remains limited as with other drugs and should only be used after shared decision making with the patients while awaiting the results of ongoing studies. As is the case with other antivirals, this drug should be used as early in the disease course as possible to achieve any meaningful effects and should be avoided in patients with severe disease. An ECG should ideally be done before prescribing the drug to measure QT interval”. QTc is a measure related to heart rates on an electrocardiogram and refers essentially to irregular heartbeats.
How does Remdesvir work in our bodies?
Remdesivir is designed to obstruct the stage of replication of the SARS-CoV2. The virus replicates by creating copies of itself, followed by the copies of copies. Basically it clones itself multiple times. Research indicates Remdesvir, cuts off the power of the xerox machine.
What is replication?
Once the virus enters the human cell, it releases its genetic material, which is then copied using the body’s existing mechanism – nothing external. it uses human proteins and their own proteins to replicate. Mainly an enzyme called RdRp (an enzyme is a kind of protein that speeds up chemical reactions within a cell). It is RdRp that makes the copies, by processing components of the RNA (Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation, and expression of genes) of the virus. The Max Planck Institute of Biophysical Chemistry in Germany described the same enzyme as the “copy machine” of the virus when they imaged the architecture of this “machine” in 3D. Science calls such an enzyme a polymerase (the p is RdRp stands for polymerase) or a Replicase and Remdesivir targets this enzyme.
What does Remdesvir do?
It acts as a trojan horse. The RNA of the virus is broken down by another enzyme with that specific function before replication. But Remdesvir, which is an inhibitor is able to mimic that function and blocks replication. “These coronavirus polymerases are sloppy and they get fooled, so the inhibitor gets incorporated many times and the virus can no longer replicate,” University of Alberta microbiologist and immunologist Matthias Götte said in a statement. The University of Alberta researchers reported in the Journal of Biological Chemistry that they found that an active compound in Remdesivir inhibits the copy machines of both viruses with the same potency and mechanism of action. Recently a paper by Chinese researchers last week has added to the emerging knowledge about the action of Remdesivir. Researchers have imaged the high-resolution structure of the SARS-CoV-2 Replicase complex, with Remdesivir bound to it. They have published their findings in Science.
Six firms to manufacture Remdesvir in India
Gilead Sciences, the owner of the patented drug Remdesvir, has signed a nonexclusive licensing agreement with Dr. Reddy’s Laboratories, Biocon firm Syngene and Zydus Cadila Healthcare. They join Hetero Labs, Jubilant Lifesciences, and Mylan, who had signed the agreement last month with Gilead. They get to sell the drug in 127 countries. As part of the agreements they have signed, the drugmakers receive technology transfer of the manufacturing process for Remdesivir and get to set their own prices for the generic product they produce, Gilead said. The licenses are royalty-free until the World Health Organization (WHO) declares the end of the Public Health Emergency of International Concern regarding COVID-19 or until a pharmaceutical product other than Remdesivir or a vaccine is approved to treat or prevent COVID-19, whichever is earlier, Gilead has said.