Gilead’s Remdesivir Receives Conditional EU Approval; Next Steps to Unlock Its Full Potential

Today, Gilead Sciences announced that the European Commission has granted conditional marketing authorization for Veklury (remdesivir) for the treatment of adult and adolescent patients with COVID-19 who require supplemental oxygen due to SARS-CoV-2 infection. In Europe, conditional marketing authorization is initially valid for one year but may be extended or converted to full marketing authorization upon submission and evaluation of additional confirmatory data. Previously, remdesivir had received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA) and special approval in Japan.

From garnering widespread attention for treating the first confirmed case of COVID-19 in the United States, as reported in a paper published in The New England Journal of Medicine this February, to gaining approval in numerous countries and regions worldwide, remdesivir has traversed its development journey under the “spotlight.” Although it has demonstrated encouraging efficacy in treating patients with severe disease, the question remains whether its currently approved indications fully realize its potential as an antiviral therapy. Today, the WuXi AppTec content team will review the development history of remdesivir and outline its future development directions.

Broad-Spectrum Antiviral Therapies Offer Hope

With increased human contact with livestock and wildlife, along with the growing ease of global travel, the emergence and even epidemic spread of new diseases are no longer rare. The “Top 10 Global Health Threats for the Next Decade,” released by the World Health Organization (WHO) earlier this year, pointed out that it is difficult to avoid a pandemic caused by a novel, highly contagious, airborne virus (most likely an influenza virus), against which the majority of the population lacks immunity. Given our shared fate, we need to better prepare for potential viral pandemics. In its strategy on emerging infectious diseases, the U.S. National Institutes of Health (NIH) has stated that the “one-bug, one-drug” approach—developing a separate drug for each disease—is insufficient; instead, broad-spectrum therapies are needed to enhance preparedness against all infectious disease threats.

Remdesivir is a drug with broad-spectrum potential against RNA viruses. The proliferation of RNA viruses relies on the replication of RNA strands carrying the viral genome, a process dependent on a class of enzymes known as RNA-dependent RNA polymerases (RdRp). These enzymes synthesize new RNA strands using existing RNA strands as templates and intracellular nucleotides as building blocks. Inhibiting RNA replication through the use of nucleoside or nucleotide analogs represents a key strategic approach in the development of antiviral therapies. Due to their structural similarity to the natural nucleotides used in viral RNA synthesis, these analogs can be incorporated by viral RdRp into growing RNA chains. However, their distinct structural differences from natural nucleotides cause them to act like a misaligned link in a bicycle chain; once incorporated, they disrupt the continued activity of RdRp, leading to premature termination of RNA strand synthesis.

▲ Structural formula of remdesivir (Image source: Meodipt [Public domain])

Remdesivir is a prodrug of a nucleotide analog. Its design primarily enhances the cellular uptake of the prodrug, thereby increasing the intracellular concentration of its triphosphate (TP) metabolite after administration (see lower left panel of the figure below), which provides more opportunities for the nucleotide analog to be incorporated into RNA chains. Meanwhile, remdesivir triphosphate exhibits high specificity for viral RNA polymerase and has minimal effects on the activity of mitochondrial polymerases and DNA polymerases in host cells, ensuring its safety profile. More importantly, RNA-dependent RNA polymerase (RdRp) is widely present in RNA viruses, including coronaviruses. Remdesivir, with its potential to inhibit RdRp activity, shows promising inhibitory effects against a broad spectrum of RNA viruses, including coronaviruses.

▲ Mechanism of Action of Remdesivir (also known as GS-5734) (Image source: Reference [21])

Furthermore, remdesivir differs from other nucleoside or nucleotide analogs in its ability to overcome the modifications made by SARS-CoV-2’s intrinsic proofreading mechanism to errors generated during RNA replication. SARS-CoV-2 possesses an inherent mechanism to correct errors arising during RNA replication, which results in a lower mutation rate compared to other viruses such as influenza virus; however, this same mechanism poses challenges for therapeutic strategies that rely on nucleoside or nucleotide analogs to introduce replication errors. Previous studies have demonstrated that remdesivir remains effective in inhibiting viral proliferation under these conditions.

Paving the Way with Key Clinical Studies

Remdesivir was able to be rapidly deployed in clinical trials during the COVID-19 pandemic, owing to its prior evaluation in clinical stages and key findings from studies targeting MERS and SARS.

Prior to this, the investigational indications for remdesivir were primarily focused on the treatment of Ebola virus infection, and Phase 2 clinical trials had been completed. Following the outbreak of the Ebola epidemic in the Democratic Republic of the Congo in 2018, the World Health Organization (WHO) initiated a multi-arm clinical trial to compare the safety and efficacy of four drugs in nearly 700 patients, among whom 175 received remdesivir. Although remdesivir demonstrated less improvement in mortality rates associated with Ebola virus infection compared to other drugs in this trial, its safety profile in humans was still confirmed to a certain extent. The paper published in the New England Journal of Medicine noted that the overall safety of the four investigational drugs, including remdesivir, was favorable and consistent with what had previously been observed in Ebola patients or healthy subjects.

Today, the European Union’s conditional marketing authorization for remdesivir was supported by the results of a Phase 3 clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). In this trial, preliminary findings indicated that remdesivir significantly shortened the time to recovery in adult patients hospitalized with COVID-19, with potential benefits in reducing mortality risk. The preliminary results of this trial were published in May in the New England Journal of Medicine. Clinical studies conducted independently by Gilead Sciences demonstrated that a 5-day course of remdesivir was comparable in efficacy to a 10-day course, suggesting that the same quantity of remdesivir could benefit a larger number of patients.

The Next Step in Unlocking the Full Potential of Remdesivir

Current research on COVID-19 indicates that, in addition to viral replication within tissues, the "cytokine storm" triggered by an overactive immune response is a significant factor contributing to severe symptoms such as acute respiratory distress syndrome (ARDS) in critically ill patients. As an antiviral therapy, remdesivir primarily functions to inhibit viral replication. Therefore, earlier treatment of COVID-19 patients to reduce viral loads before the virus triggers a severe immune response can not only prevent the onset of severe symptoms but also potentially slow the spread of COVID-19 by lowering viral levels in patients.

Previous experience with antiviral therapies (e.g., Tamiflu for influenza treatment) suggests that the “window” for effective antiviral intervention may lie in the early stages of disease. Data from clinical trials of remdesivir also indicate signs that early administration may yield better therapeutic outcomes.

However, because remdesivir is a drug that requires intravenous infusion, it is typically limited to the treatment of hospitalized patients, among whom a higher proportion have had the disease for a longer duration. Enabling early-stage COVID-19 patients to receive remdesivir will be one of the key factors determining whether this therapy can fully realize its potential.

Gilead Sciences, Inc. has planned clinical trials to evaluate the efficacy of inhaled remdesivir in treating patients with COVID-19. This new formulation, administered via nebulizer, bypasses the need for intravenous infusion, thereby removing a significant barrier to treatment. Meanwhile, Gilead Sciences will explore the possibility of treating patients in healthcare settings outside hospitals, such as infusion centers and nursing homes. In an open letter, Daniel O’Day, the company’s Chief Executive Officer, stated that initiating treatment before hospitalization is particularly important for patients at higher risk of disease progression, potentially allowing them to avoid hospital admission altogether.

In addition, the company is also exploring the effects of combining remdesivir with other therapies, including the JAK1 inhibitor baricitinib and the IL-6 inhibitor tocilizumab, which suppress patients' immune responses.

Mr. Daniel O’Day pointed out that while maximizing the potential of remdesivir to treat as many COVID-19 patients as possible, Gilead Sciences will also uphold its tradition of focusing on research into emerging viruses and continue its efforts in studying other emerging viral threats. The success of remdesivir is attributable to the extensive work the company had conducted on the drug prior to the outbreak of the pandemic. “Continuous research, iterative development, and perseverance are essential factors for scientific progress,” he said. Gilead Sciences, Inc. will not only do everything in its power to help end the current pandemic but also strive to prepare for the next one.

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[22] European Commission Grants Conditional Marketing Authorization for Gilead’s Veklury® (remdesivir) for the Treatment of COVID-19. Retrieved July 3, 2020, from https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/european-commission-grants-conditional-marketing-authorization-for-gileads-veklury-remdesivir-for-the-treatment-of-covid19

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