by Reynald Castaneda in London.
Gilead Sciences’ remdesivir is more likely to work in mild-to-moderate Covid-19 patients rather than severe cases. Given its antiviral mechanism, remdesivir has the potential to decrease viral load in less-severe patients; in those who are more critically ill, the disease’s inflammatory impact becomes the more significant factor to address.
There is both preclinical and human data showing remdesivir’s polymerase inhibitor mechanism can reduce viral load, experts said. However, all available data is still empirical in nature, and load reduction may not translate into clinically relevant outcomes like reducing hospital stay or decreasing mortality, they added.
Additionally, patients perceived as mild-to-moderate may already have inflammation, an expert said, but another noted the distinctions between the disease stages are clear. The side effects include renal and hepatotoxicity risks, which should be monitored, but the risk-benefit ratio remains on balance for investigation due to the disease severity of Covid-19.
On 3 April, the European Medicines Agency (EMA) backed remdesivir for compassionate use for Covid-19 patients. One day later, Gilead noted it had reduced remdesivir’s manufacturing timeline from one year to around six months. Remdisivir was also cleared by the FDA for emergency use on 20 March, but new applications were suspended as of 23 March after a flood of requests.
While remdesivir is under investigation in multiple trials, data from two China-based, investigator-led, Phase III trials recruiting mild-to-moderate (NCT04252664) and severe (NCT04257656) patients are highly anticipated, as they could provide the first randomised data for the drug. Results are expected this month. Gilead’s own Phase III international trials in moderate (NCT04292730) and severe (NCT04292899) cases are expected to have data in May.
Gilead did not respond to an interview request. The company has a market cap of $92.84bn.
Treating patients too late an obstacle
An antiviral like remdesivir may have the most impact early in the illness when the virus is replicating and viral load is quite high, said Dr Elizabeth Higgs, global health science advisor, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Washington, DC, US. Once inflammation occurs, it becomes the more important aspect of the disease to target, added Dr Armando Gabrielli, professor, Department of Clinical and Molecular Sciences, Marche Polytechnic University Faculty of Medicine, Ancona, Italy.
During the early stage of the disease, which spans about four to seven days after the patient contracts the virus, patients have mild-to-moderate symptoms similar to pneumonia, with recovery occurring between seven and ten days after exposure, added an EU-based critical care physician. The mild-to-moderate trial is recruiting patients at up to eight days since illness onset. The severe patient trial is recruiting patients at up to 12 days since illness onset. An interim analysis of the China-based severe trial has been completed, and the trial is proceeding as planned.
Nevertheless, while remdesivir’s overall track record signals the potential for efficacy, more Covid-19 evidence is needed, said Dr Bhaskar Dasgupta, consultant rheumatologist, Southend University Hospital NHS Foundation Trust, Southend-on-Sea, UK. So far, remdesivir’s efficacy evidence in Covid-19 patients is mostly empirical, added Dr Jean-Michel Pawlotsky, head, Department of Virology, Bacteriology-Hygiene, and Mycology-Parasitology, The Henri Mondor University Hospital, Créteil, France.
The risk of early data not translating to success in patients still remains, Higgs added. Even if there is viral load reduction, it may not lead to clinically relevant improvements like the reduction of hospital stay or disease progression, she said. The primary endpoint in the two China-based trials is time to clinical improvement up to 28 days, with the mild-to-moderate trial focusing on the normalisation of fever and respiratory rate, among others, and the severe trial looking into improvements in a patient’s intensive care unit status. Both trials have a secondary endpoint covering viral load. Due to the fast-paced nature of the pandemic, validating the viral load reduction mechanism is less important than showing whether remdesivir use can lead to clinically significant benefits, Pawlotsky agreed.
If viral load reduction does not lead to improved symptoms, it could be due to the immunomodulatory aspect of the disease already starting, Higgs added. One patient out of ten progresses to the later stage of disease wherein the body has an excessive inflammatory response, which could lead to organ failure, the physician explained. On 6 April, the Gilead-sponsored severe trial was expanded from 400 patients to 2,400 patients and arms were added to distinguish patients with and without medical ventilation, as per ClinicalTrials.gov. On the same day, Gilead increased its enrolment target in the moderate trial from 600 patients to 1,600 patients, with the primary endpoint now investigating odds of ratio for improvement on day 11. The previous endpoint was the ratio of participants discharged at day 14.
It is challenging to separate the first and second halves of the disease, said Gabrielli, adding this makes it hard to pinpoint when to switch from an antiviral to an anti-inflammatory or whether to overlap treatments. The physician disagreed, noting there is a clear line between the early and later stage. Experience between patients has been replicable, he noted. When patients do transition to the later stage, it happens ten to 14 days after symptoms appear, he added.
In the Phase II/III Ebola trial (NCT03719586) comparing remdesivir with three other therapies, there was persistent benefit with two of the other treatments, but remdesivir patients may have been sicker (Mulangu, S, et al., N Engl J Med, 2019 Dec 12, 381(24), pp. 2293–2303). Additionally, there is no clear link between Ebola and Covid-19, making remdesivir’s Ebola data difficult to extrapolate to Covid-19. Pawlotsky said.
With 97% of deaths in the Ebola trial happening within ten days of enrolment, the other two therapies have an edge as single-dose therapies, whereas remdesivir requires multiple infusions. Remdesivir was dosed for at least ten days in Ebola and is being administered between six and ten days in the China-based and Gilead-sponsored trials.
Early data supports investigation in Covid-19
Still, the Ebola trial is helpful in identifying a safe remdesivir dose for Covid-19 exploration, Higgs said. In the China-based trials, remdesivir is administered with a loading dose of 200mg, followed by 100mg once-daily doses for nine days. The aforementioned Ebola trial had the same doses, with the 100mg regimen used for 9–13 days.
Renal and liver function is closely monitored among Covid-19 patients, the physician said, noting major side effects are yet to be seen in the 15 patients he has treated with remdesivir. Covid-19 can also trigger liver injury, he said, but noted his patients have not shown any worsening in liver function. Liver toxicity could be an issue, particularly if patients are exposed to polypharmacy, said Dr Robert Gish, clinical professor of medicine, University of Nevada School of Medicine, Las Vegas, US.
Nonetheless, hepatotoxicity concerns do not weigh against investigating remdesivir’s risk-benefit ratio, Gish noted. Higgs agreed, adding 20% of Covid-19 patients get hospitalized.
There is in vitro data showing remdesivir can impact the virus SARS-CoV-1, which causes SARS, and there is a high level of similarity between SARS-CoV-1 and the SARS-CoV-2 strain, which causes Covid-19 (Sheahan, TP, et al., Sci Transl Med, 2017 Jun 28, 9(396)). It is ideal to target the polymerase in the way remdesivir does, as the polymerase is critical for viral replication, Higgs noted. Remdesivir is a nucleotide analogue inhibitor of ribonucleic acid (RNA)-dependent RNA polymerases. Polymerases, which assist with the formation of viral DNA or RNA from precursor substances, have a high chance of genetic sequence homology, which allows some extrapolation between SARS-CoV-1 and SARs-CoV-2, she added.
In Covid-19, there is emerging preclinical data showing remdesivir has an inhibitory impact, Higgs noted. In vitro testing investigating five antiviral drugs showed remdesivir could inhibit SARS-CoV-2 (Wang, M, et al., Cell Res, 2020 Mar, 30(3), pp. 269–271).
In terms of remdesivir data in Covid-19 patients, the physician pointed to a paper published in The Lancet showing remdesivir being linked to viral load decline (Lescure, FX, et al., Lancet Infect Dis, 2020 Mar 27). However, the paper noted conclusions could not be made based on three patients treated with remdesivir, all of whom were designated as severe cases. In two patients, remdesivir was initiated at the time of disease worsening, when the virus was already barely detectable. In one of them, remdesivir was discontinued after five days because of a combined alanine aminotransferase elevation and a rash. Remdesivir was discontinued after a single dose in a third patient because the patient needed renal replacement therapy.
Reynald Castaneda is a Senior Reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.