3.3 Remdesivir
Remdesivir is an investigational compound that was developed for the treatment of Ebola (Mullard, 2018; Tchesnokov, Feng, Porter, & Gotte, 2019). Remdesivir is a monophosphoramidate prodrug and acts as a broad-spectrum antiviral that can be incorporated into viral RNA (Agostini et al., 2018; Sheahan, Sims, Leist, Schafer, et al., 2020; T. K. Warren et al., 2016). Many anti-virals are proving to be ineffective against COVID-19 due to the presence of a proofreading exoribonuclease (ExoN) specific to coronaviruses, encoded in non-structural protein 14 (nsp14) (Agostini et al., 2018). Remdesivir is able to evade this viral proofreading, meaning its incorporation into viral RNA results in the inhibition of RNA-dependent RNA polymerases (RdRps), thereby preventing subsequent viral replication (Travis K. Warren et al., 2016). Furthermore, Arshad et al. suggest that the maximum serum concentration (Cmax) of remdesivir is sufficient to inhibit 90 % of SARS-CoV-2 replication, a parameter which is suspected to be of vital importance in the treatment of COVID-19 (Arshad et al., 2020).
Remdesivir is administered intravenously, with single doses ranging between 3 to 225 mg being well tolerated in Ebola patients (n = 8) (Clinical Trials.gov, 2019). Similar observations were made in the blinded, placebo-controlled multiple-dose studies, during which Ebola patients (n = 8) received an intravenous infusion of 150 mg remdesivir daily for either 7 or 14 days; only grade 1 and 2 adverse reactions were reported (Clinical Trials.gov, 2019). The proposed dosing regimen for COVID-19 patients receiving remdesivir via the UK Early Access to Medicines Scheme (EAMS) is similar to that which was evaluated for Ebola treatment: a loading dose of 200 mg on day 1, followed by 100 mg daily for 5 - 10 days depending on symptom severity (Medicines and Healthcare products Regulatory Agency, 2020b). As such, it is likely that many of the AEs observed in the Ebola study will translate to COVID-19 patients treated with remdesivir.
Mild to moderate ALT and aspartate transaminase (AST) elevations were observed in several Ebola patients during the multiple-dose study, thus reflecting observations made in human hepatocytes in vitro(Clinical Trials.gov, 2019; World Health Organisation, 2018). This is likely to be due to the high cell permeability of hepatocytes, in combination with the effective intracellular metabolism of remdesivir to its active form within the liver (World Health Organisation, 2018). Emerging data has suggested that SARS-CoV-2 may target ACE2 on hepatocytes leading to liver injury as evidenced by a significant increase in ALT and bilirubin in severe cases of COVID-19 (Guan et al., 2020). Therefore, it is likely that differentiating between COVID-19-induced transaminase elevations and those induced by remdesivir presents challenges (Bangash, Patel, & Parekh, 2020; C. Zhang, Shi, & Wang, 2020). However, a recent study found that only 4.1 % of COVID-19 patients receiving remdesivir treatment suffered serious (grade 3 or 4) transaminase elevations, with there being no significant difference between the remdesivir- and placebo-treated groups (Beigel et al., 2020). This data implies that remdesivir is relatively well-tolerated in SARS-CoV-2-positive patients. Regardless, as advised by the drug manufacturer, daily liver function tests are essential in any patients receiving remdesivir, with suggested discontinuation of the drug in patients whose ALT levels reach ≥ 5 times the upper limit of normal (ULN) (Gilead, 2020). Adhering to these guidelines is of particular importance in patients with pre-existing liver disease, or in those taking other medications which can also induce transient ALT and AST elevation (World Health Organisation, 2018).
The reported differences between preclinical and clinical data regarding the safety of remdesivir highlight the inadequacies of preclinical models in some contexts. For example, with regards to COVID-19, a concerning element of theoretical toxicity is that which affects the respiratory system. A study using mice models of Middle East respiratory syndrome coronavirus (MERS-CoV) found remdesivir improved pulmonary pathology in infected mice and rhesus monkeys, and no respiratory toxicity was observed (Gilead, 2020; Sheahan, Sims, Leist, Schafer, et al., 2020). In contrast, a respiratory safety study in rats showed that remdesivir had no impact on tidal volume or minute volume, but did increase respiratory rate, which returned to baseline by 24 hours post-dose (World Health Organisation, 2018). Clearly, increased respiratory rate is a manifestation of COVID-19, and there would be problems in assessing causality if remdesivir was also likely to cause of respiratory problems in a clinical setting. Fortunately, a recent double-blind, randomized, placebo-controlled trial showed there to be no significant differences in adverse respiratory events between the remdesivir-treated and control arms (Beigel et al., 2020). In addition to this, preclinical safety studies performed in rats and cynomolgus monkeys suggested that the kidney was the target organ for remdesivir-induced toxicity (Gilead, 2020). This was a significant concern before the initial COVID-19 clinical trials, as it is known that SARS-CoV-2 can cause acute kidney failure in severe cases (Ronco, Reis, & Husain-Syed, 2020). However, this has not been reflected in COVID-19 clinical trials, where the presence of biomarkers indicative of renal injury have not differed in patients treated with remdesivir compared to those on placebo (Beigel et al., 2020; Gilead, 2020). However, due to the inclusion of the solubility enhancer sulfobutylether β-cyclodextrin sodium (SBECD) within remdesivir formulations, remdesivir is contraindicated in patients with severe renal impairment (eGFR < 30 ml/min) (European Medicines Agency, 2020).
Finally, remdesivir is not exempt from DDIs. Co-administration of remdesivir with several antibiotics including rifampicin is contraindicated, which could cause problems for any patients being treated concomitantly for tuberculosis (Group, 2020). This occurs because of enzyme induction which reduces systemic exposure to remdesivir. A similar interaction has also been seen with enzyme-inducing anticonvulsants, including carbamazepine, phenytoin, and phenobarbital (Group, 2020), where reduction in remdesivir exposure may lead to inadequate treatment of COVID-19.