The antiviral drug remdesivir (Veklury°) was authorised in the European Union in July 2020 for use in adults and adolescents with covid-19 requiring supplemental oxygen. It only received "conditional" marketing authorisation, which means that the data underpinning its authorisation were insufficient to warrant standard marketing authorisation, but supported the plausibility of the drug's dangers being acceptable given its efficacy. In other words, great uncertainty surrounds this drug. The company that markets remdesivir has been asked to provide a great deal of additional data.

Hypersensitivity. Hypersensitivity reactions following remdesivir infusion have been reported since its market introduction in the United States in the spring of 2020. The main symptoms are hypotension or hypertension, tachycardia or bradycardia, fever, increased sweating, breathing difficulties and hypoxia, oedema, skin disorders, nausea and vomiting. The summary of product characteristics (SPC) recommends stopping the infusion immediately if signs of "clinically significant" hypersensitivity occur.

Hepatotoxicity? The "Risk Management Plan" for remdesivir, drawn up by the drug company and the European Medicines Agency (EMA), discusses the risk of hepatotoxicity. Some serious hepatic adverse events occurred in patients receiving remdesivir during its clinical evaluation, but always in a context of worsening covid-19 and concomitant use of other drugs with hepatic adverse effects. In a study in apparently healthy adults, a transient increase in liver enzymes occurred in 75% of those who received 150 mg of remdesivir for 14 days (higher than the authorised dose and longer that the maximum authorised treatment duration). As no clinical studies have been conducted in patients with hepatic impairment, the liver function of these patients should be monitored particularly closely when using remdesivir.

Pay attention to the kidneys. The Risk Management Plan for remdesivir also discusses nephrotoxicity. Renal toxicity was demonstrated in animal studies. The serious renal adverse events reported in patients receiving remdesivir during its clinical evaluation occurred in a context of worsening covid-19 and concomitant use of other drugs with renal adverse effects. Both authorised forms of remdesivir (Veklury°) contain the excipient betadex sulfobutyl ether sodium (6 g per 100 mg of remdesivir in the solution, and 3 g per 100 mg of remdesivir in the powder). This excipient is mainly excreted via the kidneys and accumulates in the body of patients with severe renal impairment. The consequences of its accumulation are unknown, but renal toxicity should be expected.

Other unanswered questions: interactions, etc. At the authorised dose, remdesivir does not appear to prolong the QT interval (an adverse effect that increases the risk of serious arrhythmia). But the effect of higher doses of remdesivir on the QT interval has not been studied in humans. The possibility that reduced remdesivir clearance prolongs the QT interval has not been ruled out.

No clinical studies have been conducted on remdesivir's interactions. In vitro, remdesivir is a substrate for various enzymes (esterases, cytochrome P450 isoenzymes, and transmembrane transporters such as P-glycoprotein). It is also an inducer of some enzymes and an inhibitor of others. Numerous pharmacokinetic drug interactions are therefore to be expected. In addition, a "major metabolite" was detected in plasma but was not identified.

Remdesivir has not been evaluated in pregnant women, and insufficient animal data are available to predict its potential effects on children exposed in utero.

One trial still in progress at the time of authorisation. The main evaluation data on the efficacy of remdesivir in patients with covid-19 are from an interim analysis of a double-blind randomised trial comparing remdesivir to placebo for a maximum of 10 days in 1063 patients with an average age of 59 years. The patients were ill enough to warrant hospitalisation and, in most cases, to also require, at the least, supplemental oxygen. The remdesivir and placebo groups, created by random assignment, were similar in terms of their other health problems, age and sex. About one-third of the patients in both groups received remdesivir or placebo for 10 days. The other drugs used were not reported, yet corticosteroid therapy for example can affect the outcome of severe covid-19 (> HERE). At the time of the analysis submitted in support of the marketing authorisation application, only two-thirds of the patients had completed the trial, lowering the quality of the evidence these results provide.

Is it effective in patients with severe disease? Based on this interim analysis, the estimated mortality after 14 days was 7% in the remdesivir group, versus 12% in the placebo group. The difference is not statistically significant (p=0.06); in other words, there is a distinct possibility that the difference is due to chance alone. The median time to clinical improvement (mainly defined as the time to hospital discharge or discontinuation of supplemental oxygen) was 11 days in the remdesivir group, versus 15 days in the placebo group (statistically significant difference, p<0.001). The difference in this endpoint was only seen among patients who were so ill at enrolment that they required, at the least, supplemental oxygen (12 days versus 18 days), but not among those with less severe disease (5 days in both groups). Other analyses found no evidence of efficacy for remdesivir in the most severely ill patients, who were receiving invasive or non-invasive ventilation at the time of their enrolment into the trial. There has even been mention of a link between remdesivir and higher mortality in patients receiving invasive ventilation at enrolment.

5 days or 10 days? Another randomised trial compared a 5-day course versus a 10-day course of remdesivir, without blinding, in 402 patients hospitalised for severe covid-19, most of whom required, at the least, supplemental oxygen, and whose average age was 62 years. Only 43% of the 10-day group actually received the treatment for 10 days, and 27% of patients in this group were treated for 5 or fewer days. The mortality after 14 days was 8% in the 5-day group, versus 11% in the 10-day group. These results are difficult to interpret because, despite the randomisation process, the proportion of patients with a severe form of covid-19 was lower in the 5-day group than in the 10-day group, with 26% of patients in the 5-day group receiving invasive or non-invasive ventilation at enrolment, versus 35% in the 10-day group. However, the possibility that prolonged treatment with remdesivir is harmful cannot be excluded. According to the SPC, the treatment duration should be at least 5 days but no more than 10 days.

More evidence awaited. In summary, as with any new drug and especially those with only conditional marketing authorisation, much remains unknown about remdesivir, both in terms of its adverse effects and its efficacy beyond a placebo effect. Caution is therefore required. Tenuous, incomplete results from a single trial showed slightly faster clinical improvement with remdesivir, but only in patients requiring supplemental oxygen, and with no proven effect on mortality. Given the current state of knowledge (and outside of the context of a clinical trial) use of remdesivir is not justified in patients who are not ill enough to need supplemental oxygen, nor in the most severely ill patients, who require invasive ventilation.

©Prescrire 13 July 2020

Sources:

• "Covid-19 : remdésivir (Veklury°) autorisé dans l'Union européenne, avec beaucoup d'incertitudes et d'inconnues" Application Prescrire 13 July 2020.
• European Commission "SPC-Veklury°" 3 July 2020. > HERE
• EMA - CHMP "Public assessment report for Veklury. EMEA/H/C/005622/0000" 25 June 2020. > HERE
• EMA - CHMP "Summary of risk management plan for Veklury (Remdesivir)". > HERE
• Beigel JH et al. "Remdesivir for the treatment of Covid-19 - preliminary report" N Engl J Med 2020 https://doi:10.1056/NEJMoa2007764. > HERE
• Goldman JD et al. "Remdesivir for 5 or 10 days in patients with severe Covid-19" N Engl J Med 2020 https://doi:10.1056/NEJMoa2015301. > HERE

For more information:

• "Covid-19: Follow Prescrire's independent, evidence-based analysis of the pandemic" > HERE