Remdesivir

Remdesivir (GS-5734, known commercially as Veklury) is an investigational broad-spectrum anti-viral drug developed by Gilead Sciences of Foster City, California. It was approved by the U.S. Food and Drug Administration for treatment of COVID-19 in late October 2020. Previously it had been distributed for clinical research trials and under "compassionate use" guidelines for experimental treatment.

Remdesivir is one of thousands of molecules compiled into a "compound library" by Gilead, which was engaged in seeking drug treatments for hepatitis C and respiratory syncytial virus. Gilead's antiviral program was directed by Tomáš Cihlář. It was identified by researchers at the U.S. Centers for Disease Control as a candidate for further investigation as a compound with the capability of interfering with self-replication in a broader range of viruses. GS-5734 was cultured into an intravenous drug which showed promise in studies led by Sina Bavari and Travis Warren of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick in Fredrick, Maryland. Those studies, notably, provided evidence that the compound was effective in combating infection from the Ebola virus in rhesus monkeys.

Gilead began to work with researchers at the University of North Carolina and Vanderbilt University to study the effects of remdesivir in in vitro and mouse models infected with the SARS-associated coronavirus (SARS-CoV) and the the MERS-coronavirus (MERS-CoV). In 2014 the National Institute of Allergy and Infectious Diseases (NIAID) awarded a five-year grant for the creation of an Antiviral Drug Discovery and Development Center (AD3C). The UAB School of Medicine was tapped to manage the administration of the center while also partnering with Southern Research on compound screening and medical chemistry, specifically targeting influenza. UAB's Richard Whitley, a member of Gilead Sciences' board of directors since 2008, was named principal investigator and program director for AD3C. Ghalib Alkhatib and James Noah led Southern Research's participation.

Gilead filed for investigational status for remdesivir in June 2015 and initiated the first human clinical trials that August, advancing manufacturing and distribution processes to facilitate that work. At the same time, under compassionate use protocols, remdesivir was used in treating a small number of individuals infected with Ebola in the Democratic Republic of the Congo. Further investigations by the National Institutes of Health identified two other more promising treatments for Ebola, however, and the remdesivir trials were suspended.

Within the Antiviral Drug Discovery and Development Center, UNC and Vanderbilt continued to focus on treatments for coronaviruses, which had been identified as a potential major global threat. These studies, supported by Gilead, showed promising results for remdesivir in primates infected with MERS. Further trials involving human subjects could not be pursued due to low infection rates.

COVID-19 treatment

When the SARS-CoV-2 virus emerged in China in 2019, those preclinical results suggested that remdesivir could be a promising candidate for treatment of the fast-spreading COVID-19 disease. Gilead provided supplies and data to the Chinese Center for Disease Control and Prevention. Phase 3 clinical trials for around 850 patients receiving a 10-day course of intravenous remdesivir began in Wuhan and Beijing by mid February. The result of a five-week randomized controlled multi-site trial with 238 subjects showed that, "remdesivir use was not associated with a difference in time to clinical improvement," with the caveat that some improvement could be shown if treatment began early in the virus' course. 18% of patients being treated with remdesivir reported adverse effects that led doctors to stop treatment early. Ultimately those trials concluded because the epidemic had largely been controlled and there were not enough eligible candidates to continue.

Gilead also supplied remdesivir to its research partners in the United States. The NIAID began a large-scale trial in February in hospitals in Nebraska and Washington, later expanding to Texas and Maryland. UAB Hospital also prepared to participate in clinical trials. Gilead began enrolling patients in its own Phase 3 clinical trials in March, using a 5-day course of treatment.

A report of the effects of "compassionate use" (not a controlled study) of remdesivir, published on April 10, 2020, found that 36 of 53 COVID-19 patients given the drug showed "clinical improvement" over the course of their treatment, while 7 of them died. National Institute of Allergy and Infectious Diseases director Anthony Fauci briefed the national press from the White House on April 29, stating that preliminary results of ongoing large-scale placebo-controlled trials in the United States, showed that, "remdesivir has a clear-cut, significant, positive effect in diminishing the time to recovery." The findings led the FDA to issue an "emergency use authorization" on May 1, allowing remdesivir to be used intravenously to treat serious COVID cases. The World Health Organization also studied the effects of four treatments being used in hospital settings and found "little to no benefit" from the drug.

Early in 2020 Gilead Sciences began preparing to manufacture and distribute remdesivir at large scale should it be approved as treatment for the pandemic disease. Following the FDA's Emergency Use Authorization, Gilead donated its entire stockpile of remdesivir to the United States for distribution to hospitals and signed agreements with five manufacturers of generic drugs, supplying 127 countries, and waiving its royalties during the duration of the global pandemic. Those agreements earned $873 million for Gilead during the 3rd quarter of 2020.

With the FDA's approval of the use of remdesivir to treat COVID-19 in October 2020, Gilead set a price for the drug at $2,340 for a five-day course.

References

• Carter, Kendra (March 19, 2014) "New antiviral drug discovery center established at UAB" UAB News
• Warren, Travis K., Robert Jordan, Michale Lo, et al (December 9, 2015) "Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates" Open Forum Infectious Diseases Vol. 2, Supplement 1.
• Warren, Travis K., et al (March 2, 2016) "Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys." Nature. No. 531, pp 381–385
• Jarvis, Lisa M. (July 6, 2016) "Study launched of Gilead’s Ebola antiviral" Chemical & Engineering News. Vol. 94, No. 28, p. 12
• Sheahan, Timothy, Amy C. Sims, Rachel Graham, et al. (June 28, 2017) "Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses" Science Translational Medicine. Vol. 9, No. 396
• Wang, Manli, Ruiyuan Cao, Leike Zhang, et al. (February 4, 2020) "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro" Cell Research. Volume 30, pp. 269–271
• Koplon, Savannah (February 7, 2020) "Investigational compound remdesivir, developed by UAB and NIH researchers, being used for treatment of novel coronavirus" UAB News
• Koplowitz, Howard (February 28, 2020) "Drug co-developed by UAB professor treating coronavirus patients" The Birmingham News
• "Development of Remdesivir" (2020) Gilead Sciences
• Pagliarulo, Ned (March 5, 2020) "A closer look at the Ebola drug that's become the top hope for a coronavirus treatment" BioPharma Dive - accessed May 1, 2020
• Ardizzone, Kathryn (March 20, 2020) "Role of the Federal Government in the Development of Remdesivir" Knowledge Economy International. Briefing Note 2020:1.
• Grein, Jonathan, et al (April 10, 2020) "Compassionate Use of Remdesivir for Patients with Severe Covid-19" New England Journal of Medicine
• Yurkanin, Amy (April 29, 2020) "Promising early results for UAB coronavirus drug could speed FDA approval." The Birmingham News
• Wang, Yeming, Dingyu Zhang, Guanhua Du, et al (April 29, 2020) "Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial" The Lancet
• "Fauci voices optimism about remdesivir as treatment for COVID-19 infection." (April 29, 2020) CBSNews.com
• Silverman, Ed (May 12, 2020) "Gilead signs licenses for generic companies to make and sell remdesivir in 127 countries." Pharmalot
• Beigel, John H.; Kay M. Tomashek; Lori E. Dodd; et al (October 8, 2020) "Remdesivir for the Treatment of Covid-19 — Final Report." New England Journal of Medicine
• Yurkanin, Amy (November 1, 2020) "Fast-tracked drug tied to Alabama is ready to battle COVID, but questions remain." The Birmingham News