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1. Inhibitors of the viral RNA synthesis SARS-CoV-2 is a single-stranded RNA betacoronavirus. Potential targets are some non-structural proteins such as protease, RNA-dependent RNA polymerase (RdRp) and helicase, as well as accessory proteins. Coronaviruses do not use reverse transcriptase. There is only a total of 82% genetic identity between SARS-CoV and SARS-CoV-2. However, the strikingly high genetic homology for one of the key enzymes, the RdRp which reaches around 96%, suggests that substances effective for SARS may also be effective for COVID19.
RdRp inhibitors 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 Authorization” 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 sub-micromolar 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. 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
COVID Reference ENG 006.9
