On May 1, the US Food and Drug Administration (FDA) issued an “urgent use authorization” for the treatment of severe cases of COVID-19 with the antiviral remdesivir. And on June 25, the European Medicines Agency (EMA) recommended to the European Commission its “conditional authorization” for these patients.
Remdesivir has generated controversy in recent days for two reasons. In the first place, its commercialization price will be just over 2,000 euros per patient , which has opened a new social debate, of a bioethical nature, on the acquisition of medicines and public health.
But, in addition, the US government has acquired 90% of the production of this drug for the next three months.
What is remdesivir and how does it work?
Remdesivir is an antiviral prodrug (a harmless substance that turns into a drug within the body when it is metabolized). It belongs to the family of nucleotide analogs and acts by inhibiting an enzyme of the virus that is essential for its multiplication. It has been shown to have in vitro activity against SARS-CoV-2:
Remdesivir was developed as a treatment for Ebola virus infection, but it also has in vitro activity against other viruses, including some coronaviruses such as the cause of MERS and SARS-CoV-2.
Is it effective and safe in COVID-19 patients?
At the end of April 2020, the preliminary results of a randomized, double-blind, controlled study conducted in Hubei, China, were published in The Lancet. 237 patients (158 treated with remdesivir and 79 treated with placebo) with severe SARS-CoV-2 infection were included in this study.
The study evaluated the “time to clinical improvement.” Although the results were not statistically significant, the ‘time to clinical improvement’ was found to be shorter in patients who received remdesivir within the first 10 days from symptom onset.
However, other studies, such as the NIAID-ACTT-1 –another multinational, randomized, double-blind and controlled clinical trial–, which evaluated the efficacy and safety of remdesivir in hospitalized patients with SARS-CoV-2 pneumonia , they did obtain statistically significant results.
In this case, patients who received remdesivir had a 31% shorter “time to clinical improvement” than those who received placebo. Specifically, “the mean time to clinical improvement” was 11 days for patients treated with remdesivir, compared to 15 days in the group of patients who received placebo.
The results also suggested a survival benefit, with a mortality rate of 7.1% in the remdesivir group, compared to 11.9% in the placebo group. This improvement was observed above all in those patients with respiratory failure (oxygen deficiency in the blood), but who did not require mechanical or extracorporeal respiration.
With regard to tolerability, the safety profile of remdesivir has not been fully characterized. Most of the clinical experience relates to its use in the control of Ebola, which differs profoundly from SARS-CoV-2. However, so far there are no safety findings that preclude its use in COVID-19 patients.
Among the concerns to consider in patients treated with remdesivir are renal and liver function, which should be monitored before and during treatment. Compassionate use data in 61 critically ill COVID-19 patients treated with remdesivir, published in April in the New England Journal of Medicine , revealed that the most common adverse effect was increased levels of liver enzymes, observed in 23% of patients, arterial hypotension being the second (8% of patients).
On the other hand, remdesivir has some structural and functional similarities with another antiviral drug, tenofovir, which has been confirmed to be nephrotoxic, both in patients with chronic hepatitis B type and in animal models. In humans, remdesivir is largely eliminated by the kidneys, which could lead to organic accumulation of the drug in patients with kidney failure.
Less severe gastrointestinal adverse effects, such as nausea and diarrhea, have also been reported in 3% to 5% of treated patients, although these effects could also be associated with COVID-19 symptoms.
How and when is it administered?
Remdesivir is given through an IV drip line. Its use is limited to hospital centers where patients can be closely watched, monitoring liver and kidney function, before and during treatment. Treatment should start with a 200 mg infusion on the first day, followed by a 100 mg infusion daily for at least 4 more days. Never for more than 10 days.
Why your conditional authorization?
Evaluation of preliminary quality, manufacturing, preclinical and clinical data, as well as safety data from experience with the use of this medicine in compassionate use programs, began in April 2020. With all these data, the EMA has proposed the conditional authorization of this drug, which implies that the efficacy and safety data have to be expanded, so further research with this drug must be continued.
Conditional authorization of a drug means that it is considered to meet an unmet medical need to the extent that the public health benefit of its immediate availability outweighs the uncertainty arising from the limited data available.
However, the marketing laboratory (in this case Gilead Sciences), must commit to providing more clinical data that complements the current information on the efficacy and safety of the drug. In this sense, only when these data are positive will the complete and definitive authorization be granted. Otherwise, it will be withdrawn from the market.
What can we expect from this antiviral drug?
Remdesivir has opened an important door to the treatment of COVID-19. It is the first authorized agent that acts directly on the virus. But, although its efficacy has been initially demonstrated in seriously or very seriously ill patients, its safety profile has not been fully clarified.
Currently, there are more than seven clinical trials around the world that are evaluating this antiviral, and the Johns Hopkins University considers remdesivir as the most promising drug at the moment for the treatment of COVID-19.
For all these reasons, the scientific community, together with the health and regulatory authorities, must closely monitor all the clinical data that will be provided in the coming months to definitively confirm the suitability of this treatment.
Francisco López-Muñoz. Associate Professor of Pharmacology and Vice-Rector for Research and Science, Camilo José Cela University
Jose Antonio Guerra Guirao Professor of Pharmacology and Toxicology. Pharmacy faculty. Complutense University of Madrid., Complutense University of Madrid
This article was originally published on The Conversation. Read the original.
