Based on promising laboratory data, researchers and doctors have initiated a randomised clinical trial on treating people with COVID-19 with amantadine, an anti-influenza drug.
The battle against COVID-19 continues.
Doctors and researchers are striving to understand and combat COVID-19 and SARS-CoV-2, which have dominated the global agenda for almost 2 years.
Denmark is also involved in these efforts, and researchers from the University of Copenhagen in collaboration with biotech company Synklino have discovered that amantadine, which is normally used to treat influenza A or Parkinson’s disease, inhibits two ion channels in SARS-CoV-2.
These initial data have been so promising that the researchers, together with doctors at the Department of Infectious Diseases at Hvidovre Hospital near Copenhagen, have initiated a randomized clinical trial using amantadine to treat people with COVID-19.
The research team will probably learn by spring 2022 whether amantadine, which has been on the market for more than 45 years, can attack an Achilles heel in SARS-CoV-2 and thus contribute to ending the pandemic.
“The big story is that our study may suggest that we can repurpose a drug used for combating influenza and Parkinson’s disease to treat people with COVID-19. Further, getting regulatory approval for an existing drug to treat people with COVID-19 may be very rapid if it turns out to have the effect that we hope for,” explains a researcher behind the discovery, Mette M. Rosenkilde, Professor, Department of Biomedicine, University of Copenhagen. However, she continues, “The data from the randomised clinical trials are needed to finally establish the in vivo impact of our findings.” The study has been published in Communications Biology.
Discovered two ion channels in SARS-CoV-2
Mette M. Rosenkilde and her colleagues have been searching for new drug targets in the SARS-CoV-2 genome and have specifically looked for known and novel ion channels encoded on the surface of the virus.
In connection with the outbreaks of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, researchers found that these coronaviruses express various surface proteins that are promising to target with drugs to inhibit them. One of these viral proteins is the envelope (E) protein, which is well conserved across many coronaviruses, including SARS, MERS and SARS-CoV-2.
The researchers hoped to find more of these vulnerable ion channels in SARS-CoV-2.
In reviewing the genome, the researchers looked for the genetic code for motifs typically found in transmembrane proteins.
The study revealed that, in addition to the two known ion channels, the E protein and the 3a protein, SARS-CoV-2 also has two other ion channels, the Orf7b and Orf10 proteins, that may be interesting drug targets.
Amantadine blocks the two ion channels
The researchers identified the two novel ion channels and then screened various drug databases for drugs known to inhibit these ion channels. This led them to amantadine, which can block both the Orf10 protein and the E protein.
To confirm the drug’s effectiveness, the researchers expressed the proteins in frogs’ eggs and treated the cells with amantadine, which blocked the ion channels.
“Interestingly, studies on SARS show that blocking the function of protein E or changing its genetic sequence causes less severe illness in mice. The same is probably true for SARS-CoV-2, since the Protein E from these two viruses is almost identical. We therefore hope that amantadine may also be effective for people with COVID-19,” says Mette M. Rosenkilde.
Other studies have indicated effectiveness
Mette M. Rosenkilde and colleagues are not the first to suggest using amantadine to treat people with COVID-19.
Two rather small retrospective studies in Poland, in which researchers examined disease development among people treated with amantadine for Parkinson’s disease, suggested that amantadine may lead to less severe illness. In contrast, a study from Mexico City did not find any significant improvement in people with COVID-19 treated with amantadine.
“These studies examined treatment with amantadine retrospectively and cannot be used for anything other than to suggest that amantadine has an effect. A randomised and placebo-controlled clinical trial is therefore required to determine whether amantadine can slow the development of illness in COVID-19,” explains Mette M. Rosenkilde.
Results in spring 2022
Doctors and researchers at Hvidovre Hospital are carrying out the randomised and placebo-controlled clinical trial led by Nina Weis , Professor and Chief Physician at the Department of Infectious Diseases.
In the trial, 242 people who test positive for SARS-CoV-2 are being given amantadine or a placebo and followed-up for 90 days to determine effectiveness and the development of sequelae and side-effects. Severe lung disease was an exclusion criterion because the researchers hope that treatment with amantadine can prevent progression to serious illness.
The trial is in full swing, and Mette M. Rosenkilde expects that it will be completed by spring 2022.
The researchers and doctors will then be able to determine whether the effect they found on the ion channels in the laboratory are reflected in clinical effectiveness.
“Determining the potential is difficult, and we are very cautious on expressing the impact as we do not know this until the randomised clinical trial is complete. Then the results will speak for themselves,” concludes Mette M. Rosenkilde.
