Repurposed Drugs to Fight SARS-CoV-2, Remdesivir - Part 2

Part 2, Remdesivir

Among the list of potential drugs to treat COVID-19 remdesivir, an antiviral drug developed by Gilead Sciences to treat Ebola and Marburg virus infections, has emerged as the front runner.

In addition to being active against filoviridae (Ebola and Marburg), remdesivir (development code GS-5734) has broad antiviral activity against a whole host of viruses such as Lassa hemorrhagic fever virus, Junin virus which causes Argentine hemorrhagic fever, coronaviruses such as MERS and SARS and others.

From Wikipedia, the free encyclopedia

During the West Africa Ebola Virus epidemic (2013-2016) Gilead and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) collaborated to find ways to treat Ebola patients. Phase I testing with remdesivir was performed in 2015, followed by phase II in 2016. A phase III study in 2018, however, showed that two other treatments were superior to remdesivir, leading to the reassignment of patients receiving remdesivir to one of the other two drugs.

(In case you really want to know, the more efficacious drugs were: Mab114, a monoclonal antibody developed in a collaboration between researchers at the National Institute of Health Vaccine Research Center and the Institut National pour la Recherche Biomedicale in the Democratic Republic of Congo, and REGN-EB3, a cocktail of three monoclonal antibodies, invented by Regeneron.)

Remdesivir as COVID-19 Treatment

In the frantic search for COVID-19 treatments, remdesivir quickly emerged as one of the leading candidates. Studies already conducted in 2017 and 2018 showed the drug’s ability to inhibit coronaviruses. Initially, the drug was tested in a small number of patients in collaboration with Chinese authorities starting in January 2020 and clinical trials began on February 6, 2020. Gilead announced two more phase III trials to evaluate safety and efficacy of remdesivir in adult COVID-19 patients in late February.

Controversy erupted when the FDA provided remdesivir orphan drug status on March 23, 2020. COVID 19 at that time formally fulfilled the requirements of an orphan disease, i.e. a rare disease that fewer than 200,000 patients in the US suffer from. Drugs for rare diseases stand a high risk of being unprofitable and therefore receive incentives under the Orphan Drug Act of 1983. However, given the explosive growth rates of COVID-19 cases and the expectation that the number of cases will soon exceed the threshold of 200,000, public outcry over the designation resulted in Gilead asking the FDA to rescind the orphan drug status just days later.

Mechanism of Action

Remdesivir is a nucleotide analog, that works by inhibiting the synthesis of new RNA strands needed for the virus to multiply. Coronaviruses are enveloped positive RNA viruses that replicate using an RNA-dependent RNA polymerase complex (a lot more detail can be found here). This is where remdesivir interferes: it mimics adenosine, one of the building blocks of RNA. As remdesivir is integrated into the RNA, instead of adenosine, the RNA-dependent RNA polymerase complex is rendered inactive and with that the virus is unable to replicate.

As of late March 2020, two more clinical studies are enrolling patients to further test efficacy and safety of remdesivir in patients suffering from COVID-19.

Adverse Events

Information on adverse events associated with remdesivir are difficult to find, as the drug has not been approved yet and has so far been used in clinical studies to treat hemorrhagic fevers with high mortality rates and very severe courses of disease.

The WHO state that “The diastereomeric prodrug mixture (remdesivir and its diastereomer at phosphorous in a ~1:1 ratio), and the parent nucleoside, GS-441524, have a low potential for off-target activity” (more information can be found here).

An unpublished paper “circulating ahead of an official peer review” raised initial concerns in mid-March about possible gastrointestinal adverse effects. However, until more studies are completed no firm statements can be made about the safety profile of remdesivir.

Who is Who in Remdesivir Research

Here is our Special TTL listing remdesivir experts and leading institution