Remdesivir vaults into lead in COVID-19 treatment
As the global fight against COVID-19 heats up, remdesivir is leading the way in the search for a COVID-19 treatment for which the world yearns.
Data from two multinational SIMPLE studies showed that remdesivir led to better clinical recovery in hospitalized patients with moderate or severe COVID-19 illness than standard of care (SOC).
Fuelled by data from these studies and the ACTT-1 study, a new drug application to the US FDA has been filed just recently for remdesivir in the treatment of COVID-19. The drug was previously granted Emergency Use Authorization by the FDA.
Meanwhile, remdesivir is already approved for severe COVID-19 in certain countries in Asia, including Japan, Taiwan, and Singapore.
How long and when to give: SIMPLE got answers
In the phase III SIMPLE study on patients with moderate COVID-19, a 5-day treatment course with remdesivir led to significantly better clinical status distribution at day 11 compared with SOC (odds ratio [OR], 1.65; p=0.02).
Participants in the study were COVID-19 patients hospitalized with evidence of pneumonia but without reduced oxygen levels. The initial phase involved 596 patients randomized 1:1:1 to receive intravenous remdesivir for 5 days or 10 days or SOC. An extension phase to enrol another 1,000 patients is ongoing. [JAMA 2020;doi:10.1001/jama.2020.16349]
The primary endpoint was clinical status at day 11, assessed based on a 7-point ordinal scale. Clinical status ranged from hospital discharge to increasing need for supplemental oxygen or ventilatory support to death.
While the 10-day treatment course of remdesivir also improved clinical status at day 11, the difference was not statistically significant compared with SOC (p=0.18).
Both the 5-day and 10-day remdesivir treatment courses were well tolerated in general. The most commonly reported adverse events (AEs) included nausea, diarrhoea, and headache.
“These study results offer additional encouraging data for remdesivir, showing that if we can intervene earlier in the disease process with a 5-day treatment course, we can significantly improve clinical outcomes for these patients,” said study investigator Dr Francisco Marty from Brigham and Women’s Hospital, Harvard Medical School in Boston, Massachusetts, US.
In the SIMPLE-Severe study comparing 10-day vs 5-day remdesivir in COVID-19 patients with severe* disease not requiring mechanical ventilation, the investigators found that the shorter course of treatment was sufficient. [N Engl J Med 2020;doi:10.1056/NEJMoa2015301]
At day 14, there was no significant differences in clinical status distribution between the 5-day and 10-day groups after adjusting for baseline clinical status (p=0.14).
Other outcomes such as all-cause mortality, time to clinical improvement, and recovery were also similar between the two treatment courses.
“Identifying the shortest duration of effective treatment with remdesivir is an urgent medical need,” said the investigators. “A shorter course of treatment without a loss of efficacy could reduce hospital stays and potential adverse events and could extend the limited supply of remdesivir available during this pandemic.”
The rates of any AEs were similar between the two groups (70 percent vs 74 percent) — with nausea, worsening respiratory failure, elevated alanine aminotransferase level, and constipation being the most common.
“However, these results cannot be extrapolated to critically ill patients receiving mechanical ventilation,” Marty and co-authors pointed out.
“Patients who progress to mechanical ventilation may benefit from 10 days of remdesivir treatment; further evaluation of this subgroup and of other high-risk groups, such as immunocompromised persons, is needed to determine the shortest effective duration of therapy,” they suggested.
In another comparative analysis of patients with severe COVID-19 in the SIMPLE-Severe trial, remdesivir was associated with significantly improved clinical status at day 14 when compared with a separate real-world retrospective cohort of patients with similar disease severity who received SOC in the same time period (recovery rate, 74.4 percent vs 59.0 percent).
In addition, the risk of mortality at day 14 was reduced by 62 percent with remdesivir compared with SOC in the retrospective cohort (adjusted OR, 0.38; p=0.001).
An important first step
Writing in an accompanying editorial, Drs Raphael Dolin and Martin Hirsch commended that conducting randomized clinical trials (RCTs) for an unknown disease at multiple sites globally during a time of pandemic with restrictions on movement was “an extraordinary achievement.” [N Engl J Med 2020;doi:10.1056/NEJMe2018715]
“Remdesivir [represents] an important first step,” hailed Dolin and Hirsch from Beth Israel Deaconess Medical Center and Massachusetts General Hospital, respectively, both in Boston, Massachusetts, US.
In the first RCT report of an effective therapy for COVID-19, the ACTT-1** showed that 10-day remdesivir significantly shortened the time to recovery vs placebo in hospitalized COVID-19 patients (median, 11 vs 15 days; rate ratio for recovery, 1.32; p<0.001). [N Engl J Med 2020;doi: 10.1056/NEJMoa2007764]
Notably, the benefit was most pronounced in patients with an ordinal score of 5 (requiring oxygen, but not mechanical ventilation yet) at baseline, on a 7-point ordinal scale.
“The findings in the trial suggest that the timing of initiation of treatment with an antiviral such as remdesivir, as well as the underlying clinical status of the patient, may have important effects on the outcomes of therapy,” wrote Dolin and Hirsch.
“Studies of combination therapy with other antivirals and anti-inflammatory agents in appropriate sequence are of high priority, and plans for such studies are already under way,” they stated.