# While clinical trials suggest ‘remdesivir’ is not very effective in treating Covid-19, recent studies have shown that it does block Coronavirus activity. That apparent contradiction makes the antiviral drug even more controversial. Remdesivir is an experimental drug developed by biotechnology company Gilead Sciences (under the brand name Veklury) in collaboration with the Centres for Disease Control and Army Medical Research Institute of Infectious Diseases. https://www.gilead.com/purpose/advancing-global-health/covid-19 It’s one of many drug candidates originally designed in response to the threat from emerging diseases caused by RNA viruses — germs like the one behind the 2002 SARS outbreak — that have the potential to cause a global pandemic. https://en.wikipedia.org/wiki/2002%E2%80%932004_SARS_outbreak Such ‘broad-spectrum’ drugs target features shared by a wide range of disease-causing germs. In remdesivir’s case, that’s RNA — the virus’ genetic material. The drug proved ineffective against the Ebola virus, however, and yet was still subsequently repurposed for SARS-CoV-2 coronavirus. https://www.drugsincontext.com/the-journey-of-remdesivir:-from-ebola-to-covid-19/ ## Remdesivir’s Effectiveness News media prematurely reported that patients were responding to treatment. https://www.statnews.com/2020/04/16/early-peek-at-data-on-gilead-coronavirus-drug-suggests-patients-are-responding-to-treatment/ But the published data lated showed that “remdesivir was not associated with statistically significant clinical benefits [and] the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.” https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext The controversy surrounding remdesivir therefore revolves around whether the drug is actually an effective treatment. What’s weird about remdesivir is that it hasn’t been held to the same standards as other drug candidates. Covid-19 vaccines have been developed 10 times faster than traditional drugs, but they’ve passed the phase-3 clinical trials that test whether a potential medicine is both safe and effective in thousands of people. https://www.forbes.com/sites/jvchamary/2020/11/30/coronavirus-vaccine-development-manufacturing-distribution-vaccination/ Normally, a drug is only approved for use by a regulatory body like the US Food and Drug Administration if it meets those two criteria for safety and efficacy. Nonetheless, in October 2020, remdesivir was granted approval by FDA based on promising data from relatively small trials involving about 1000 participants. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19 Early studies produced conflicting evidence on remdesivir’s effectiveness. Some found that patients who received the drug recovered faster and fewer died, while others showed that it didn’t reduce the length of hospitalisation or death rate. https://jamanetwork.com/journals/jama/fullarticle/2769870 But a large-scale analysis by the World Health Organisation’s Solidarity trial consortium has cleared-up the confusion. Based on interim results from studying more than 5000 participants, the international study concluded that remdesivir “had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.” https://www.nejm.org/doi/10.1056/NEJMoa2023184 So remdesivir isn’t very effective and, as a consequence, WHO recommends against the use of remdesivir in Covid-19 patients. https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients ## The Cost of Remdesivir The drug is administered over 5 or 10 days. A five-day course of treatment costs around $2600 per person so, for a hospital with hundreds of patients, that would amount to millions of dollars. https://www.bmj.com/content/371/bmj.m4057 That price could be considered cost-effective if remdesivir’s use was limited to moderate or severe disease and it saved lives, but the drug’s also available for milder cases and, as WHO’s study found, it doesn’t seem to be a lifesaving drug. https://icer.org/news-insights/press-releases/icer-provides-second-update-to-pricing-models-for-remdesivir-as-a-treatment-for-covid-19/ So what next for remdesivir? Following WHO’s finding, an article in the *British Medical Journal* highlighted another antiviral as a cautionary tale: oseltamivir or ‘Tamiflu’, a drug that aimed to block the influenza virus. https://www.bmj.com/content/371/bmj.m4457 During the early 2000s, governments started stockpiling Tamiflu, paying billions to its manufacturer, pharmaceutical firm Roche. In 2013, independent researchers gained access to Roche’s unpublished data, revealing that the drug caused many side effects and only shortened the duration of flu symptoms by a few hours. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375804/ The *BMJ* article implies that the story of remdesivir is another scandal waiting to happen. Given that remdesivir is expensive and doesn’t seem to save lives, does it have any value? Maybe, but not as a medicine — recent research suggests scientists should at least keep studying how it works in order to develop better drugs. ## How Remdesivir Works Remdesivir doesn’t prevent people from being infected by the SARS-CoV-2 virus. Whereas a vaccine is designed prompt your immune system to recognise the spike protein that allows the Coronavirus to invade cells — and protect people from infection — antivirals such as remdesivir aim to disrupt the virus’ ability to replicate, to slow its spread and give your body extra time to develop immunity. https://www.forbes.com/sites/jvchamary/2020/11/29/coronavirus-immune-system/ Coronaviruses use RNA as genetic material — not the DNA used by cells — which means they need a special molecular machine to copy their genes when producing new virus particles. That machine, ‘RNA polymerase’, is targeted by remdesivir. Two studies have now revealed how remdesivir blocks SARS-CoV-2 at the molecular level. First, chemical engineers at the University of Chicago found that remdesivir is better at reducing virus replication than two similar antivirals, ribavirin and favilavir. Their computer models suggest that remdesivir is the best at binding and destabilising the RNA polymerase, which explains why it beats other drugs. https://pubs.acs.org/doi/10.1021/acscentsci.0c01242 In the second new study, researchers at the University of Texas at Austin used ‘cryogenic-electron microscopy’ (cryo-EM) to take snapshots of the structure of the molecules involved in replication as they would interact in a Covid patient. https://www.sciencedirect.com/science/article/pii/S1097276521000551 After adding remdesivir to RNA polymerase, the cryo-EM images showed that the drug acts like a blockage in a photocopier, getting stuck in the RNA polymerase. When four molecules of remdesivir get between the gears of the virus’ polymerase machine, its ‘paper’ copies — the genetic material of RNA — can no longer pass through, stalling the copying process. That leads us to why it’s worth studying remdesivir. As structural biologist David Taylor explains, “We were able to identify the point where that paper jam happens […] If we want to make the blockage even worse, we could do so.” https://www.eurekalert.org/pub_releases/2021-01/uota-sdh012821.php One of the drug’s flaws is its (possibly toxic) high dosage over a short time, which contributes to adverse side effects. By tweaking remdesivir’s structure, scientists may be able to make it block the RNA polymerase machine with fewer molecules, which would then allow the drug to be delivered in a smaller dose. In fact, Gilead Sciences has already isolated a compound similar to remdesivir, GS-441524, which costs less and is easier to manufacture and administer. While remdesivir must be injected, GS-441524 could be taken in pill form. More of it reaches the lungs — the main site of infection — too, leading researchers to state that “GS-441524 is superior to remdesivir for Covid-19 treatment.” https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316 Despite being expensive and ineffective at treating Covid, remdesivir’s true value will be to help researchers develop better medicines. As SARS-CoV-2’s genetic material mutates to create new strains of the virus — and variants of Covid-19 — we may need antivirals to buy us time if those new strains end-up evading current vaccines.