The key role of antivirals in COVID-19 treatment (remdesivir)

The key role of antivirals in COVID-19 treatment (remdesivir)

How do you tackle a completely new deadly virus? Which are the first weapons to be used against the virus and its mortal spread? Once the SARS-CoV-2 coronavirus was described and isolated, expert virologists from all over the world were sure they had to start with what they already knew. Whether it was on a clinical trial or accumulating dust like an old book on a laboratory shelf, the first move to do was the reposition and repurpose of other existing drugs. This is how the antiviral remdesivir came into play.

The biopharmaceutical company Gilead Sciences, together with the US Army and the CDC (the US Centers for Disease Control and Prevention), originally started to evaluate the antiviral remdesivir, which had previously been used in clinical trials during the Ebola outbreak of 2014. The company then began distribution for compassionate use in late January of this year, and also started clinical studies with COVID-19 patients.
In July 2020, and in a decision that has caused a heated debate in the scientific and policy-making worlds, the drug became the first medicine to receive official marketing authorisation both by the Food and Drug Administration (FDA) in the United States and the European Medicine Agency (EMA).

The latest results from the aforementioned trials – the Adaptive Covid-19 Treatment 1 (ACTT-1) , a phase 3, randomized, double-blind, placebo-controlled trial – from October 8th, showed that remdesivir only worked well in severe patients with pneumonia in need of supplementary oxygen. The data indicated that patients that used remdesivir had a recovery time of around 10 days, in comparison with the 15 days of those who were treated with a placebo. In the severe cases group, time to recovery was around 11 days for those treated with remdesivir and 18 days for those treated with a placebo.

Last 15th of October, another study, still pending to undergo peer review, about remdesivir’s efficacy to reduce mortality was published. The Solidarity study, an international clinical trial to find an effective treatment for COVID-19 coordinated by the World Health Organisation (WHO), presented its interim results in form of a preprint report published at MedRxiv. It enrolled almost 12,000 patients in 405 hospital sites in 30 countries establishing a global platform to help reach patients as the epidemic evolved. The study found that the “four treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients”. The trial will now consider new antivirals and anti-SARS-CoV2 monoclonal antibodies for evaluation, according to the WHO Press Office.

Dr Juan Pablo Horcajada, Hospital del Mar, Spain : “What we already know from the ACTT-1 trial is that remdesivir shows a reduced duration of the disease without manifesting a reduction in mortality either. It is a positive clinical effect, and it gives the medical community enough reason to continue using it while new and more successful molecules come up. If remdesivir had no beneficial effect, then it would have to be discontinued.” – Read the full interview of Juan Pablo Horcajada

Antivirals are a key part of the solution

Although coronaviruses have been known since the 1960s, it was not until the 2003 SARS outbreak and the 2009 MERS virus outbreak that these types of viruses showed a capacity to produce high mortality rates. On the basis of the experience of those years, scientists from all over Europe are asking for more resources and dedicated plans to find a cure or potential treatment against all coronavirus infections. It seems imperative to find a vaccine to end the pandemic. In the meantime, we need to find a drug to treat the thousands of patients that are now in intensive care because of this disease. So far there are over 315 treatments and 201 vaccines under development in the world, both in preclinical and clinical evaluation. And antivirals are very important players in this fight. The idea of attacking the reproductive machinery of a pathogen came to light thanks to George Hitchins and Gertrude Elion back in the 1940s. In those years, Elion devised a chemical compound that had some effect against viruses. However, its high levels of toxicity discouraged her from following this research path for almost 20 years. She resumed this research later, and in 1978 the first antiviral drug was approved for the market. It was acyclovir, an antiviral for use against herpes viruses. Hitchins and Elion were both awarded the Nobel Prize in Physiology or Medicine in 1988 for their contributions to drug development.

Professor Martijn J. van Hemert, Leiden University, The Netherlands : “I think there is too much focus on vaccines. The need for antivirals should be emphasised more, since they have various advantages. Ideally antivirals should be active against a broad spectrum of viruses, not only against SARS-CoV-2, but also against other coronaviruses.” – Read the full interview of Martijn J. van Hemert

The key aspect of antivirals is that they do not boost the immune response of the body, like a vaccine does, but they attack the virus by preventing it from reproducing inside cells. Scientists now aim to design an antiviral that offers broad protection against all coronaviruses. This means that when another outbreak happens, we will then have something to treat the first patients with. Antivirals are currently being used to treat several diseases caused by herpes viruses, hepatitis viruses, the Ebola virus and HIV.

What else do we have?

COVID-19 causes a severe inflammatory phenomenon. That’s why a main source of treatments is common anti-inflammatory drugs like corticosteroids, which are readily available and inexpensive. Along with the recent results of the recovery trial in the UK, on 2 September the results of seven randomised clinical trials that evaluated the efficacy of corticosteroids in 1 703 critically ill patients with COVID-19 were published. On the same day, the World Health Organisation (WHO) published a clinical guide recommending the use of systemic corticosteroids for the treatment of patients with severe or critical COVID-19.

Dr Juan Pablo Horcajada : “There are now many different molecules on the way to being tested in humans, but clinical trials are very complex and resource-intensive, so not every hospital is capable of performing them. We must choose the molecules with the best chance of targeting the virus and, even better, also fighting the inflammatory process. But we need more time to do it properly.”

Now Europe is going through a second wave of the pandemic, with curfews and quarantines being set in place by many governments and number of cases. The number of cases has skyrocketed but the mortality rates are nowhere near to what we had in March, April and May. We are now better prepared, we know what measures work, and what we can do to protect ourselves from the virus. But we need to find a cure, both to alleviate mild and severe cases, and also to address the social, economic and political issues. Remdesivir didn’t prove to be the magic silver bullet we all were expecting at the beginning of the crisis, but the strategy behind this antivirals research, with the goal of a general treatment for all types of coronaviruses, could be a good solution.

What is next?

At the end of October, the European Medicines Agency (EMA) took a step further in implementing extra transparency measures for COVID-19 medicines and published both the clinical data in support of the authorisation of Veklury (remdesivir) and information on the COVID-19 treatments and vaccines that have been receiving scientific advice or informal guidance from EMA’s pandemic Task Force (COVID-ETF).

The EMA is currently “waiting to receive all the data from the WHO solidarity study to make a proper, updated regulatory assessment of remdesivir and to draw further conclusions about the effectiveness of the drug” – says Marco Cavaleri, Head of the EMA COVID-EFT. In this context, he adds that “it has to be kept in mind that while ACTT-1 is a placebo-controlled study with a primary clinical endpoint of time to recovery, the WHO Solidarity trial is an open label pragmatic study with limited data collection and a primary clinical endpoint of mortality in hospital. Based on these elements, the Solidarity study does not appear adequate to measure time to recovery and was not designed to test for this outcome. A lack of effect on mortality was already visible in the ACTT-1 study. The current approval by the EMA is based on the benefit in time to recovery”.

On 20 November WHO issued a conditional recommendation against the use of remdesivir in COVID-19 patients.
The decision was taken after the final editing of this text. We will continue to closely follow the developments in the coming weeks and to look for the opinions of experts and scientists in the field.

Useful links :
• EU project : Corona Accelerated R&D in Europe (CARE) coordinated by Institut National de la Santé et de la Recherche Médicale
• Swift Coronavirus Therapeutics Response (SCORE) c oordinated by Academisch Ziekenhuis Leiden (NL)
• Update on remdesivir – EMA will evaluate new data from Solidarity trial