Remdesivir ineffective against COVID-19? Perhaps it is not taken the right way

As a new experimental broad-spectrum antiviral developed by Gilead Sciences, chemically, remdesivir is essentially a nucleotide analogue, and its pharmacological mechanism of action is to “adulterate” the RNA synthesis process of the virus to ultimately inhibit the RNA-dependent RNA synthetase’s function and thus inhibit virus replication and growth. It was initially developed to mainly target the Ebola virus that has resulted in a virulent infectious disease, and the study found that it was effective in inhibiting the SARS or MERS virus in respiratory epithelial cells. As a result, it was widely used in the treatment of COVID-19 during the COVID-19 outbreak and was once pronounced as “people’s hope” or “weiruyi” in China according to its English pronunciation, showing the high expectations.

The final report on treating COVID-19 with remdesivir showing that it outperformed the placebo

The New England Journal of Medicine (NEJM) published a final report on the efficacy of remdesivir in treating COVID-19 on Nov. 5 this year. The report first mentioned that although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (COVID-19), no antiviral agents have yet been shown to be efficacious. The results of the report clearly show that: remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had signs of lower respiratory tract infection. Specifically, a total of 1,062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo. The patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15. Furthermore, model estimates based on the data obtained predicted that 15 days after treatment, mortality in the remdesivir group would be 25%-43% lower than in the placebo group, while the serious adverse event rate in the remdesivir group would be lower than in the placebo group. Those results show the excellent efficacy of remdesivir, and the debate about the efficacy of remdesivir seems to be coming to a conclusion.

Only a randomized, placebo-controlled, double-blind trial is the gold standard for testing the efficacy of remdesivir

Why this current, latest study in the NEJM is called the final report? Why previous studies were not the final reports? Because this was a randomized, placebo-controlled, double-blind trial, the random method eliminated human disturbance, the placebo eliminated the influence of patients’ psychological or other factors on the results, and the double-blind approach made it impossible for either patients or physicians to know whether the “fake medicine – placebo” or the “real medicine – remdesivir” was used, further eliminating the external disturbance, and physicians did not know which drug each patient used until the day the trial was over. As such, this approach is considered the gold standard for testing the efficacy of pharmaceutical products. Anyway, if this approach is not used, there may be biases in determining the efficacy of pharmaceutical products, such as the classic “survivor effect”. To put it simply, drug A may have no therapeutic effect and may even be slightly toxic, but the survivors believe that it worked, and as they can publicize it, the efficacy of drug A may be exaggerated. However, people who are poisoned and killed or failed treatment with drug A could not speak because they are already dead or died of diseases, resulting in the toxic effects of drug A to be ignored.

Gilead is anxious as the WHO has recommended against the use of remdesivir in COVID-19 patients in the same period

Almost simultaneously with the release of the final paper in the NEJM on the validation of the efficacy of remdesivir, the World Health Organization (WHO) Guideline Development Group published an article in the British Medical Journal/BMJ stating that the antiviral drug remdesivir is not suggested for patients admitted to hospital with COVID-19, regardless of how severely ill they are, because there is currently no evidence that it improves survival or the need for ventilation in COVID-19 patients. Moreover, this article published by the WHO is not a research paper but a dynamic guideline. However, also according to the guideline, it is not that remdesivir has no benefit in the treatment of COVID-19, but that in the current situation, there is no valid evidence that the drug is effective in curing COVID-19, namely, there is no evidence that remdesivir is ineffective, and there is no sufficient evidence that it is effective.

The molecular weight of remdesivir is only 602. Overall, it is still a small molecule drug. An important feature of small molecule drugs is their controllable quality, ease of industrialization and mass production and extremely low final costs. As a result, Gilead’s remdesivir could become a global new drug far superior to the common super-blockbuster drugs and bring the company huge excess profits. However, remdesivir has three disadvantages in the treatment process, which may be among the reasons why it is currently not recommended by WHO: (1) it requires intravenous infusion and cannot be taken orally, and the intravenous infusion is difficult to operate; (2) it is still patented, expensive, and may cause a serious expense burden on patients; (3) it has not been mass-produced and is not widely accessed by people around the world. And Gilead has expressed their disappointment at the WHO’s guideline and expressed that remdesivir’s clinical treatment data are still being collected, its clinical performance has been good so far, and remdesivir is still the only reasonable choice for COVID-19 patients.

Although remdesivir has received a full approval from the U.S. FDA for the treatment of COVID-19, the method may be wrong. 

Remdesivir has received a full approval from the U.S. FDA for the treatment of COVID-19 last month, following a previous approval for authorized limited use, however, the authorization this time is still intravenous infusion that may not bring better efficacy. We know that the first organ the novel coronavirus will infect is the lung which is also the organ where critical tissue will be subsequently infected and severe pneumonia will be developed. As such, here is a hypothesis: why not deliver remdesivir directly to the patient’s lungs? Is this feasible? In fact, it is. The drug delivery method can be aerosolized administration. However, it is not very common in the treatment of adults and has traditionally been used mainly in the treatment of children with asthma. Aerosolized administration can aerosolize glucocorticoids, bronchodilators, antibiotics, mucolytics, etc. by machines to produce aerosol and directly deliver the aerosol to the lungs. If you are looking for trustworthy medical product suppliers, then Pharmasources would be your best choice.

Compared to systemic drug delivery (oral or intravenous), the important advantages of aerosolized administration include at least three: (1) direct drug delivery to the site of action can reduce the dose of the drug required to achieve therapeutic effects, which can save money and reduce the toxic and side effects of high doses; (2) aerosolized bronchodilator administration acts faster than intravenous administration and can improve lung pathology more rapidly; (3) direct administration to the lungs can make the drug enriched in the lungs, where it is tens to hundreds of times more concentrated than the same dose of the drug intravenously administered, and this concentration may be critical for inhibiting the novel coronavirus in the lungs, especially at the early stage of novel coronavirus infection, where it may be effective in reducing the pulmonary immune response and the rate of developing into severe disease.

Summary

The idea of changing the administration method of remdesivir from intravenous administration to more convenient handheld aerosolized administration is not groundless because many antivirals for children are administered using this method, and most have achieved very good therapeutic results. Furthermore, according to previous treatment results for SARS and MERS, aerosolized interferon has a significant advantage over other similar drugs. Therefore, by updating the administration route, there is no doubt that the use of remdesivir via nebulizer will have a significant and very meaningful influence on the future treatment of COVID-19.

About the author: 

Shanghai Xiaoyaoshi, a doctoral candidate, focusing on research related to clinical and molecular pharmacology.