2.1. Remdesivir (Veklury, GS-5734)
Remdesivir is an adenosine monophosphate derivative and nucleotide-based antiviral prodrug (Figure 2). Remdesivir received, in May 2020, an emergency use authorization from the U.S. FDA for the treatment of laboratory-confirmed or suspected COVID-19 illness in children and adults hospitalized with severe disease [25]. The parenterally administered drug is being developed by Gilead Sciences, U.S., and has broad-spectrum antiviral activity [26]. It was first studied in 2016 as a potential treatment for Ebola virus [27]. In addition to its activity against SARS-CoV-2, remdesivir has a potential to treat a variety of infections caused by RNA viruses, including SARS-CoV and MERS-CoV [28].
The drug is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells (Figure 2). The triphosphate metabolite acts as a competitive inhibitor of RdRp and thus eventually causes chain elongation termination, which decreases the viral RNA replication [29]. The termination is delayed and happens after the addition of more nucleotides (between 3 and 5). Therefore, remdesivir is described as a direct antiviral agent acting as a delayed chain terminator [30,31]. Importantly, remdesivir avoids proofreading by viral exoribonuclease [28,32]. Currently, remdesivir is being evaluated as a treatment for COVID-19 patients in about 15 studies across the globe. The drug is being tested alone or in combination with merimepodib (NCT04410354; n = 40), tocilizumab (NCT04409262; REMDACTA; n = 450), or baricitinib (NCT04401579; ACTT2; n = 1034). In particular, merimepodib is another antiviral agent that is inhibitor of inosine monophosphate dehydrogenase. The enzyme is required for the synthesis of guanine nucleotides. Merimepodib consequently inhibits the synthesis of DNA and RNA, leading to antiviral and immunosuppressive effects. Thus, remdesivir and merimepodib is a dual-acting antiviral combination with immunosuppressive activity.
Remdesivir itself demonstrated in vitro activity against Vero E6 cells infected with SARS-CoV-2 with an EC50 value of 0.77 µM (CC50 > 100 µM) [33]. Remdesivir also exhibited in vitro activity against SARS-CoV and MERS-CoV in multiple in vitro systems, including primary human airway epithelial cell cultures with sub-micromolar IC50 values [28]. Remdesivir was also effective against pre-pandemic bat-CoVs, bat-CoVs, and contemporary circulating human coronaviruses in primary human lung cells suggesting a broad-spectrum anti-coronavirus activity. In a mouse model of SARS-CoV, the prophylactic and early therapeutic use of remdesivir significantly decreased the lung viral load and improved the respiratory functions as well as the overall clinical signs of the disease [28]. Furthermore, remdesivir with interferon (INF)-b demonstrated better antiviral activity compared to lopinavir/ritonavir with INF-b in vitro. Compared to lopinavir/ritonavir/INF-b, the prophylactic and therapeutic use of remdesivir also more effectively diminished the pulmonary viral loads and improved the pulmonary function in mice model of MERS-CoV [34]. The efficacy of the prophylactic and therapeutic use of remdesivir was also demonstrated in the rhesus macaque model of MERS-CoV infection [35]. Very recently, remdesivir was also shown to inhibit SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). In mice infected with a chimeric SARS-CoV encoding RdRp, therapeutic administration of remdesivir diminished lung viral load and improved pulmonary function compared with vehicle-treated mice [36].
As far as clinical trials in humans, a randomized, placebo-controlled, double-blind trial in hospitalized adults (n = 236) with severe COVID-19 in China initially revealed that the median time to improvement was not substantially different in the remdesivir group (200 mg on the first day, and then 100 mg/day for 9 days) from that of the placebo group. The mortality rate was also similar in the two groups [37]. Yet, the trial was criticized for being insufficiently powered. Later, a phase 3 randomized, open-label trial in adults (n = 397) hospitalized with severe COVID-19 sponsored by Gilead revealed that the time to clinical improvement for 50% of patients was 10 days in the 5-day treatment group relative to 11 days in the 10-day treatment group. The dose regimen used was 200 mg on day 1, followed by 100 mg/day for total of 5 or 10 days. At day 14, about 64.5% of the patients in the 5-day group and 53.8% of the patients in the 10-day group achieved clinical recovery. Patients treated with remdesivir within 10 days of symptoms onset achieved better outcomes relative to those treated after more than 10 days of symptoms [38]. Similar results were obtained in hospitalized adults (n = 1600) with moderate COVID-19 (NCT04292730). In an uncontrolled study of hospitalized COVID-19 patients (n = 61), most patients needed less oxygen support after receiving remdesivir [39]. Importantly, a phase 3 adaptive, randomized, placebo-controlled study sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in hospitalized adults (n = 1063) indicated that: (a) the patients in the remdesivir group had shorter median time to recovery (11 days) than the patients in the placebo group (15 days) and (b) remdesivir may decrease the mortality rate from 11.6% in the placebo group to 8% in the treatment group [40]. As of now, the COVID-19 Treatment Guidelines Panel of the U.S. National Institute of Health recommends remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease (requiring supplemental oxygen or on mechanical ventilation or extracorporeal membrane oxygenation). The Panel also indicates that there are no sufficient data to recommend either for or against the use of remdesivir in patients with mild or moderate COVID-19 [41]. Of note, the U.S. FDA warns against the concomitant use of remdesivir and chloroquine or hydroxychloroquine owing to in vitro evidence which suggests that chloroquine blocks the intracellular activation of remdesivir [42]. Moreover, data from the manufacturer’s compassionate use program suggested no safety concerns were identified for remdesivir in pediatric, pregnant, or postpartum patients [43].