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Is Remdesivir the miracle cure or a short term cure for COVID-19?

Reporter: Irina Robu, PhD

 

Updated on 5/23/2020

 

New England Journal of Medicine

SOURCE

https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Disclosures

The trial was sponsored and primarily funded by the National Institute of Allergy and Infectious Diseases, the NIH, and funded in part by the NIAID and the National Cancer Institute, NIH. The trial has also been funded in part by the governments of Japan, Mexico, Denmark, and Singapore. The trial site in South Korea received funding from the Seoul National University Hospital. Support for the London International Coordinating Centre was also provided by the United Kingdom Medical Research Council.

Beigel disclosed no conflicts of interest.

Other co-authors disclosed support from NIH/NIAID/DMID, University of Minnesota, Medical Research Council U.K., Novo Nordisk Foundation, Simonsen Foundation, GSK, Pfizer, Boehringer Ingelheim, Gliead, MSD, Lundbeck Foundation, Merck, Sanofi-Pasteur,Cepheid, Ellume, Genentech, Janssen, ViiV Healthcare, Integrum Scientific LLC, UCL, Bristol University, Gilead Sciences Europe, ECDC, EU Social funds and National resources.

One co-author is an employee of the U.S. government.

Abstract

BACKGROUND

Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.

METHODS

We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

RESULTS

A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).

CONCLUSIONS

Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705. opens in new tab.)

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Remdesivir Data from NIAID Trial Published

— “Not a panacea” or a “cure-all,” expert cautions

Peer-reviewed findings were published late Friday from one of the key trials of remdesivir, perhaps the most promising antiviral agent for COVID-19, confirming and extending topline results announced a month ago via press release.

Hospitalized patients with COVID-19 who received remdesivir had a median recovery time of 11 days versus 15 days with placebo (rate ratio for recovery 1.32, 95% CI 1.12-1.55, P<0.001), reported John Beigel, MD, of the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues.

Mortality estimates by 14 days were lower for the remdesivir group compared to placebo, but non-significant (HR for death 0.70, 95% CI 0.47-1.04), the authors wrote in the New England Journal of Medicine.

Interestingly, when researchers examined outcomes on an 8-point ordinal scale, they found patients with a baseline ordinal score of 5 had a rate ratio for recovery of 1.47 (95% CI 1.17-1.84), while patients with a baseline score of 7 had a rate ratio for recovery of 0.95 (95% CI 0.64-1.42).

Some of these data were released by the NIAID on April 29, but without further details such as 95% confidence intervals. On May 1, the FDA agreed to let remdesivir be used clinically under an emergency use authorization. Since then, however, clinicians and other researchers have clamored for a fuller report, to help guide their clinical practice. For example, questions were raised as to whether particular subgroups got more benefit from the drug than others.

David Aronoff, MD, of Vanderbilt University Medical Center in Nashville, who was not involved in the research, noted the drug seemed more effective when given to patients who weren’t as severely ill, earlier in the course of disease. He added this wasn’t surprising, given remdesivir’s mechanism of action as an antiviral, which works by blocking the virus from replicating.

“The drug doesn’t affect the host, it only affects the virus. What seems to cause major problems late in the course of disease is the inflammatory response to the initial damage the virus causes,” he told MedPage Today.

Aronoff likened the virus to an arsonist setting fires, and antivirals like remdesivir as the police trying to catch the arsonist before they set more fires.

“But once the building is on fire, it doesn’t matter where the arsonist is,” he noted.

This is why combining a drug to address the viral response with a drug to address the host response may be critical to treating the virus. Aronoff cited the NIAID’s ACTT-2 trial in progress, which will examine combination therapy with remdesivir and anti-inflammatory drug, baricitinib, versus remdesivir alone.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/86670?xid=NL_breakingnewsalert_2020-05-23&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=RemdesivirAlert_052320&utm_term=NL_Daily_Breaking_News_Active

 

Is Remdesivir the miracle cure or a short term cure for COVID-19?

Reporter: Irina Robu, PhD

 

In 1947, amid the “Golden Age” of antibiotic research that yielded many of the medicines used against bacteria such as chloramphenicol, a molecule that could combat a wide array of bacteria from different families. It was among the first FDA-approved broad-spectrum antibiotics used against typhus/meningitis. Now, chloramphenicol’s side effects make it a last-resort drug but it remains invaluable against a host of bacterial infections.
Viruses are more slippery targets than bacteria and they are a hundred times smaller and consist only of bare-bones cellular machinery. There are simply fewer targets at which to aim antivirals, especially for drugs that would shoot for the rare viral components that remain common across diverse types of viruses. Scientists call this virus-pinpointing model the “one drug, one bug” approach. An antiviral’s mechanism can’t be too generic, either.

Even with that, there is no common mechanism to target all viruses but instead researchers hope to expand the existing list of broad-spectrum antivirals and find more medicines that work on all viruses of a certain family. This reality makes the search for treatments for SARS-CoV-2 all the more challenging. Presently, no broad-spectrum antiviral is accepted for the treatment of all coronaviruses of which a new strain has driven the current pandemic.

With no specific antiviral drug for treatment of patients with severe COVID-19, scientists are rushing to find a solution. Yet, remdesivir’s journey from hypothesis to treatment is unparalleled. The drug was originally investigated by Gilead as a treatment for another lethal viral disease, Ebola. Remdesivir, a nucleoside analogue prodrug has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.

However, Gilead was unwilling to give up on its investment in the drug and remained hopeful that the drug might be useful in treating COVID-19. In collaboration with Chinese researchers, the National Institute of Allergy and Infectious Diseases (NIAID) and the pharmaceutical company behind the drug, Gilead, all launched studies of remdesivir’s efficacy in treating COVID-19. Based on those encouraging results in May 1, the FDA issued an emergency-use authorization that permits doctors to treat severely ill COVID-19 patients with remdesivir. Japanese health officials issued a similar clearance days later.

On top of the biological challenge of finding new broad-spectrum antiviral drugs lies an economic one, partly because there is little financial incentive to develop broad-spectrum drugs against emerging diseases. And with all the government backed research, there is no guarantee that pharma companies have enough incentive to continue working on research. Yet, broad-spectrum antivirals are not miracle drugs, but they can be a helpful addition to a toolbox that is currently sparse.

Remdesivir’s potential first drew public attention in October 2015 during an Ebola outbreak in West Africa that claimed more than 11,000 lives. Remdesivir subdues a virus by interfering with replication. First, the body changes remdesivir into an imposter. It becomes what’s called a nucleoside analog, a genetic doppelganger that resembles adenosine. When the virus replicates, it weaves this analog into the new strand of genetic material. Nevertheless, the analog’s molecular makeup differs from real adenosine just enough to grind the copying process to a halt.

As COVID-19 swept the globe, scientists led an international trial of remdesivir as a treatment option. EIDD-2801, another treatment option has demonstrated broad-spectrum antiviral potential, as well as an ability to defend cells from SARS-CoV-2. Yet, the best treatment for COVID-19 can be remdesivir, EIDD-2801 or any single antiviral at all. Even with that, broad spectrum antivirals can be invaluable in the short-term.
The early success of remdesivir suggests that broad-spectrum antivirals will get their moment in the scientific limelight. After a pandemic pass, though, the rush interest about a multipurpose treatment diminishes.

SOURCE

https://www.smithsonianmag.com/science-nature/remdesivir-works-against-many-viruses-why-arent-there-more-drugs-it-180974859/?utm_source=smithsoniandaily

https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19

 

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