Is there no hope?
All drugs against covid failed in a clinical trial under the auspices of WHO, even remdesivir. What does this mean – and what can we hope for now?
Experts of the World Health Organization (WHO) have published the results of a major international clinical trial of drugs against coronavirus infection – organized in early spring by the Solidarity program. These results are still preliminary, and the article has not passed the review procedure, but there is not much to hope for: none of the drugs included in the study did not bring any significant benefit to patients. The most insulting situation is with the antiviral drug remdesivir – a lot of hopes were pinned on it, and the first results of other studies seemed to confirm them. But new data suggests otherwise.
Medusa asked Ilya Yasny, Candidate of Chemical Sciences, Head of Scientific expertise of the Inbio Ventures venture fund, to tell about how to understand this contradiction, what exactly the WHO has investigated and how things are with alternatives now.
Remdesivir was one of the main hopes for COVID-19 and showed encouraging results
Usually, the development of new drugs takes ten years and in the vast majority of cases ends in failure. In the conditions of the COVID-19 pandemic, humanity cannot afford such a luxury, so from the very first months of it, they tried to use existing medicines against the new coronavirus. However, despite the danger of the virus, hasty registration and widespread introduction of insufficiently tested drugs into practice can be no less dangerous. The fact that some drug has previously helped against HIV, malaria or influenza does not mean that it will be effective and safe for patients with coronavirus. Even if the substance has shown activity in cell cultures, its chance to reach the market, according to statistics, is less than 1%. The balance of benefits and risks should be established in large-scale, well-planned clinical trials.
The story of the rise and fall of hydroxychloroquine is widely known. However, in the eyes of specialists, there was no take-off: the drug showed some effectiveness in poorly planned studies on a small number of patients, and in larger-scale studies it was expected to fail, including preventive reception in patients who came into contact with patients.
The first results of double-blind randomized controlled trials (the gold standard in drug development) began to appear at the end of April. In particular, many experts pinned their hopes on the low-molecular-weight viral RNA polymerase inhibitor remdesivir, although it has not shown particular effectiveness either in the treatment of hepatitis C or against the Ebola virus.
The first such study on 1,062 patients conducted by the US National Institutes of Health (NIH) showed that remdesivir in severe patients reduces the median recovery time from 15 to 10 days. It also showed a tendency to decrease mortality from 11.6 to 8%. It became clear that although this drug is not a panacea, it can be useful for the treatment of hospitalized patients (it was not considered for outpatient treatment, since the drug is injectable).
Based on these results, remdesivir received a temporary permit for severe patients in the USA on May 1. Then remdesivir received approval on similar terms and in The European Union, and in some other countries. In August, the temporary permit was extended to all hospitalized patients, regardless of the severity of the disease.
The final results of this study were published recently, on October 8, and there was a decrease in mortality from 11.9 to 6.7% on day 15 and from 15.2 to 11.4% on day 29.
A WHO study suggests that remdesivir does not seem to be of any use – or there is very little of it
And like a bolt from the blue on October 15, the interim data of the SOLIDARITY study, which has been conducted by WHO since March 2020 (Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results), were published. Up to October 4, 11,330 people participated in the study, of which 2,750 received remdesivir, 954 – hydroxychloroquine, 1,411 – a combination of lopinavir and ritonavir ("Kaletra"), 2,063 – interferon-beta 1a, 4088 – placebo.
Disappointing news: none of the drugs showed superiority over placebo in terms of mortality, speed of cure, or duration of hospitalization. No one expected anything from hydroxychloroquine, lopinavir/ritonavir and interferon – everything became finally clear about the first two drugs back in July, at the same time their dosing was stopped as part of the study. But more was clearly expected from remdesivir. But the conclusion says that the data obtained are incompatible with the hypothesis of a significant effect of the drug on mortality. Simply put, if there can be any benefit from remdesivir in covid, it is very small.
Gilead, the developer of the drug, has issued a press release criticizing the results of Solidarity, drawing attention to the fact that, firstly, the publication was published in the form of a preprint, that is, it has not yet been independently reviewed; and secondly, that the study was open (that is, patients and the doctors knew which drug who was receiving). The authors of the publication, in turn, note that the openness of the study should not significantly affect such a parameter as mortality. In addition, we note for ourselves that the situation when blinding works in favor of the drug is very rare – usually on the contrary, in an open study it seems that the drug works, but in a blinded effect disappears. Therefore, experts agree that the chances that the effect of remdesivir is real after such results are small.
The remaining uncertainty with remdesivir is now limited only to whether it helps at least a little or does not help at all. The Solidarity study continues and is recruiting 2,000 people a month, they will receive remdesivir, monoclonal antibodies and other therapies that deserve attention. Remdesivir is also being studied in several studies in combination with other drugs. For example, in September, Eli Lilly issued a press release stating that the combination of remdesivir and baricitinib (an anti-inflammatory drug recently registered against rheumatoid arthritis) slightly reduces the time to recovery. However, a press release is still not a full-fledged article or even a preprint, and the details of the study are not yet available.
Research on antitumor drugs continues, but only mass vaccination can fundamentally change the course of the pandemic
What options for COVID-19 drug therapy remain now? Another large study of drugs already approved for other diseases is RECOVERY, conducted in the UK. It also showed the uselessness of hydroxychloroquine in early June, but in mid-June there was good news: the mortality rate of severe patients on ventilators (there were 2104 people) receiving dexamethasone was 29.3% compared with 41.4% in the placebo group. The drug did not work on those who did not need respiratory support. This is also good news because dexamethasone is a very cheap and widely available drug, a well–known corticosteroid used for inflammation and excessive immune response.
But dexamethasone does not make sense to use at an earlier stage of the disease, and even more so for prevention. It has a number of undesirable side effects, one of which is the suppression of immunity, which is completely unnecessary in the fight of the body against the virus at an early stage. Only when the disease enters a phase in which the immune system that has gone out of control harms the body's own tissues, the use of dexamethasone is fully justified from the point of view of the mechanism of pathology: we know that excessive activation of the immune system is the cause of complications and death of severe patients with COVID-19. However, it is worth repeating that theoretical considerations alone, why the drug can help, even well-founded ones, are not enough to recommend the drug for use. Only further qualitative clinical studies can answer the question whether the drug will really help patients, and not harm them – and it is desirable that these studies be confirmed in different centers and by different groups of scientists. A good illustration is the H1N1 flu pandemic and the history of the outbreak of the first SARS-CoV-1: in both cases, corticosteroids have already been tried for treatment, but no clear positive result was obtained then.
The RECOVERY study is ongoing, at the moment patients receive either the antibiotic azithromycin, or tocilizumab (an antibody that reduces the immune response, so far it has shown mixed results), or blood plasma of recovered patients, or a combination of antibodies against coronavirus.
Now, among the studied drugs, many hopes are pinned on monoclonal antibodies, which showed the first promising results. However, it must be recognized that although they, like any other investigational drugs, have the potential to reduce mortality or accelerate recovery, they still cannot change the course of the pandemic. This requires the development of vaccines that reduce the transmission of the virus from person to person. And until then, only the already familiar masks, distancing and other anti-epidemic measures remain.
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