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WHEN COVID-19 began its march across the world, so did a desperate hunt for a treatment. Not only would finding one save lives, the knowledge that it was available would also allow countries to relax the lockdowns which are strangling economies everywhere. Attention has focused especially on whether existing drugs—which have already gathered evidence of safety in human trials—might be repurposed for the job.
Particular attention has been paid to remdesivir, an antiviral agent developed by Gilead, a Californian firm, to treat Ebola—but which was sidelined when it was found to be less effective for that purpose than alternatives. On April 29th America’s National Institute of Allergy and Infectious Diseases, which has been running randomised controlled trials of this drug, said preliminary data showed that it worked. On May 1st the country’s Food and Drug Administration said it would permit emergency use of the substance.
Remdesivir is a nucleotide analogue—in other words, its structure mimics one of the chemical letters that make up the alphabet of the virus’s genetic code, which is written in a molecule called RNA that is similar to, but not identical with, DNA. The ill-fitting chemical letter gums up the virus’s replication mechanism. Remdesivir’s effect was not dramatic—it improved patients’ recovery time from 15 days to 11 days, and there was no statistically significant difference in death rates between treated and untreated patients—but it was real. A four-day reduction in stay-length will reduce the disease’s burden on hospitals.
Full data from the trial have not yet been published, something which makes those not involved in it nervous. Robin Ferner, a clinical pharmacologist at the University of Birmingham, in England, for example, says the lack of data is “unhelpful and confusing” for doctors who want to know if it would be a good treatment and when to give it. Some doctors think that the drug will need to be given earlier than it was in the trial, when a patient’s viral load is rising, to have more of an effect. Also, outsiders cannot currently analyse the different groups of patients involved, to make sure that those who did not receive treatment were well matched with those that did. If, for example, those in the treatment group were healthier than those who were left untreated as a control, that would make the drug look more effective than it actually is.
There is another problem, too. Supplies of the drug are limited, and it takes time to make more. Gilead has been working hard since the beginning of the year, when the idea that remdesivir might work against covid-19 was first mooted, to increase production. The goal is to have made 1m treatment courses by the end of the year.
Remdesivir may then be a beginning. Its eventual value, though, is likely to be as an arm of a combination therapy. Other drugs which might form part of such a therapy include further antiviral drugs, and also anti-inflammatory medicines.
One candidate anti-inflammatory treatment is Actemra (tocilizumab), made by Roche and currently prescribed for arthritis. Many of those most seriously affected by covid-19 are killed by an overreaction of their immune system, called a cytokine storm, that leads to massive inflammation of the lungs and consequent respiratory failure. Cytokines are signalling molecules secreted by the immune system in order to regulate itself. A storm occurs when uncontrolled levels of cytokines are released. Actemra blocks the cellular receptors for a cytokine called interleukin-6.
In a recent trial of Actemra, 129 moderately or severely affected covid-19 patients who had developed pneumonia showed that it reduces covid-19 deaths in the worst-affected patients. The big challenge with anti-inflammatory treatments is knowing when to give them. Applied too soon, they will reduce the immune response that is needed to tame the virus. For that, doctors will need to look carefully at the data from the Actemra trial. These, though, have not yet been published either.■