Remdesivir (Veklury®)

Remdesivir (RDV) is a nucleotide analog and the prodrug of an adenosine C nucleoside which incorporates into nascent viral RNA chains, resulting in premature termination. It received an “Emergency Use Authorisation” from the FDA in May and a so-called “conditional marketing” authorization from the EMA in July.

In vitro experiments have shown that remdesivir has broad anti-CoV activity by inhibiting RdRp in airway epithelial cell cultures, even at submicromolar concentrations. This RdRp inhibition works in rhesus macaques (Williamson 2020). The substance is very similar to tenofovir alafenamide, another nucleotide analogue used in HIV therapy. Remdesivir was originally developed by Gilead Sciences for the treatment of the Ebola virus but was subsequently abandoned, after disappointing results in a large randomized clinical trial (Mulangu 2019). Resistance to remdesivir in SARS was generated in cell culture but was difficult to select and seemingly impaired viral fitness and virulence. However, there is a case report describing the occurrence of a mutation in the RdRp (D484Y) gene following failure of remdesivir (Martinot 2020). Animal models suggest that a once-daily infusion of 10 mg/kg remdesivir may be sufficient for treatment; pharmacokinetic data for humans are still lacking.

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Outlook | References

Safety was shown in the Ebola trial. In the Phase III studies on COVID-19, an initial dose of 200 mg was started on day 1, similar to the Ebola studies, followed by 100 mg for another 4-9 days. The key trials are listed here:

  • Compassionate Use Program: this was a fragmentary cohort (Grein 2020) on some patients (only 53/61 patients were analyzed) with varying disease severity. Some improved, some didn’t: random noise. We believe, for a number of reasons, that this case series published in the New England Journal of Medicine is a cautionary tale for “science in a hurry”, arousing false expectations. It might have been preferable to postpone the publication (Hoffmann 2020).
  • NCT04257656: This multicentre RCT at ten hospitals in Hubei (Wang 2020) randomized a total of 237 patients with pneumonia, oxygen saturation of 94% or lower on room air and within 12 days of symptom onset to receive 10 days of single infusions or placebo. Clinical improvement was defined as the number of days to the point of a decline of two levels on a six-point clinical scale (from 1 = discharged to 6 = death). Patients were 65 years old (IQR 56–71), and many were co-treated with lopinavir (28%) and corticosteroids. The trial did not attain the predetermined sample size because the outbreak was brought under control in China. However, remdesivir was not associated with a difference in time to clinical improvement. Day 28 mortality was 14% versus 13%. Of note, the viral load decreased similarly in both groups. Some patients with remdesivir had dosing prematurely stopped due to adverse events (12% versus 5%, mainly gastrointestinal symptoms and increases of liver enzymes). The positive message from this trial is that time to recovery was “numerically” shorter in the remdesivir group, particularly in those treated within 10 days of symptom onset.
  • SIMPLE 1: in this randomized, open-label RCT in 397 hospitalized patients with severe COVID-19 and not requiring IMV, clinical improvement at day 14 was 64% with 5 days and 54% with 10 days of remdesivir (Goldman 2020). After adjustment for (significant) baseline imbalances in disease severity, outcomes were similar. The most common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT level (7%), and constipation (7%). Because the trial lacked a placebo control, it was not a test of efficacy for remdesivir. An expansion phase will enroll an additional 5,600 (!) patients around the world.
  • The second open-label SIMPLE trial, NCT04292730 (GS-US-540-5774), evaluated the efficacy of two remdesivir regimens compared to standard of care (SOC) in 584 hospitalized patients with moderate COVID-19, with respect to clinical status assessed by a 7-point ordinal scale on day 11. Clinical status distribution was significantly better for those randomized to a 5-day course of remdesivir compared with those randomized to SOC (Spinner 2020). According to the authors, however, this “difference was of uncertain clinical importance”. The difference for those randomized to a 10-day course (median length of treatment, 6 days) compared with standard of care was not significant. By day 28, 9 patients had died: 2 (1%) and 3 (2%) in the 5-day and 10-day remdesivir groups, and 4 (2%) in the SOC group, respectively. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients, compared with SOC.
  • ACTT (Adaptive COVID-19 Treatment Trial): The conclusion of the final report for this double-blinded RCT that had randomized 1,062 patients throughout the world, was remarkably short: remdesivir “was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection” (Beigel 2020). Median recovery time was 10 versus 15 days. On an eight-category ordinal scale, patients who received remdesivir were more likely to improve at day 15. The benefit in recovery persisted when adjustment was made for glucocorticoid use. The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15. Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
  • WHO Solidarity Trial Consortium 2020: Not yet peer reviewed, but important: In SOLIDARITY, 11,266 adults (405 hospitals in 30 countries) were randomized, with 2750 allocated to remdesivir, 954 HCQ, 1411 lopinavir/r, 651 interferon plus lopinavir/r, 1412 only interferon, and 4088 no study drug. Kaplan-Meier 28-day mortality was 12%. No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration.

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What comes next? Several additional trials are ongoing. Let’s wait for the results, before we throw remdesivir into the dump. According to a recent review, remdesivir (5 days) should be prioritized for hospitalized patients requiring low-flow supplemental oxygen as it appears that these patients derive the most benefit (Davis 2020). The data also support some benefit in hospitalized patients breathing ambient air (if there is adequate drug supply). Current data do NOT suggest benefit for those requiring high-flow oxygen or mechanical ventilation (non-invasive or invasive). It has become “clear that treatment with an antiviral drug alone is not likely to be sufficient for all patients” (Beigel 2020).

Of note, some new ideas on remdesivir as an inhalation therapy have been published (Contini 2020). Local instillation or aerosol in the first phase of infection, both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication and the risk of severe COVID-19. Gilead is working on this (knowing that “early intravenous infusions” are not feasible).

By Christian Hoffmann