Off-patent liver drug could be repurposed to prevent Covid-19 - including future variants, University of Cambridge scientists discover

An off-patent drug used to treat liver disease could be repurposed to prevent Covid-19 - and it is thought it may work against future variants of the virus too, Cambridge researchers believe.

An innovative mix of mini-organs, donor organs, animal studies and patients were used to show how the drug known as ursodeoxycholic acid (UDCA) is able to ‘lock’ up the doorway used by the SARS-CoV-2 virus to enter our cells.

Since it targets this receptor on the surface of our cells, known as ACE2, rather than the virus itself, it should protect against new variants of the virus as well as other coronaviruses that could emerge.

Larger clinical trials will be needed to confirm the findings, which were published on Monday (December 5) in Nature, but if they do, the drug could prove to be an affordable and effective way of protecting those for whom the Covid-19 vaccines are either ineffective or inaccessible.

Dr Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke’s Hospital, led the research in collaboration with Prof Ludovic Vallier, of the Berlin Institute of Health at Charité.

Dr Sampaziotis said: “Vaccines protect us by boosting our immune system so that it can recognise the virus and clear it, or at least weaken it. But vaccines don’t work for everyone – for example patients with a weak immune system – and not everyone have access to them. Also, the virus can mutate to new vaccine-resistant variants.

“We’re interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We’ve discovered a way to close the door to the virus, preventing it from getting into our cells in the first place and protecting us from infection.”

Since the drug is off-patent, it means pharmaceutical companies can create generic version of it, reducing its price, potentially making it ideal for developing countries awaiting vaccines.

Dr Sampaziotis added: “We have used UDCA in clinic for many years, so we know it’s safe and very well tolerated, which makes administering it to individuals with high Covid-19 risk straightforward.

“This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against Covid-19.”

The discovery came after Dr Sampaziotis worked with ‘mini-bile ducts’ to study diseases. These organoids - clusters of cells that grow in culture to take on a 3D structure with the same functions as the actual organ - demonstrated that a molecule known as FXR found in large amounts in them regulate the viral ‘doorway’ ACE2 directly, effectively opening and closing it. They then showed UDCA, which is used to treat a liver disease known as primary biliary cholangitis, ‘turns down’ FXR and closes the ACE2 doorway.

The new study, published in Nature, shows the same approach can be used to close the ACE2 doorway in mini-lungs and mini-guts – the two main targets of SARS-CoV-2 – and prevent viral infection.

The team then teamed up with Prof Andrew Owen, from the University of Liverpool, to show the drug prevented infection in hamsters exposed to the virus - the ‘gold-standard’ model for pre-clinical testing of drugs against SARS-CoV-2.

The hamsters treated with UDCA were protected from the delta variant of the virus, which at the time was new and partially resistant to existing vaccines.

Prof Owen said: “Although we will need properly-controlled randomised trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against Covid-19 and complement vaccination programmes, particularly in vulnerable population groups.

“As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants.”

Further work with Prof Andrew Fisher from Newcastle University and Prof Chris Watson from Addenbrooke’s Hospital tested the approach with a pair of donated lungs not suitable for transplantation, which were kept breathing outside the body with a ventilator and a pump to circulate blood-like fluid through them.

Both lung were exposed to SARS-CoV-2 and the one lung given the drug did not become infected, while the other did.

Prof Fisher said: “This is one of the first studies to test the effect of a drug in a whole human organ while it’s being perfused. This could prove important for organ transplantation – given the risks of passing on Covid-19 through transplanted organs, it could open up the possibility of treating organs with drugs to clear the virus before transplantation.”

The Cambridge team collaborated next with Profr Ansgar Lohse, from the University Medical Centre Hamburg-Eppendorf in Germany, who said: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting that the virus would have fewer opportunities to break into and infect their nasal cells – the main gateway for the virus.”

Looking at data for patients already taking UDCA for liver conditions also showed they were less likely to develop severe Covid-19 and be hospitalised than those not receiving it.

First author and PhD candidate Teresa Brevini, from the University of Cambridge, said: “This unique study gave us the opportunity to do really translational science, using a laboratory finding to directly address a clinical need.

“Using almost every approach at our fingertips we showed that an existing drug shuts the door on the virus and can protect us from Covid-19. Importantly, because this drug works on our cells, it is not affected by mutations in the virus and should be effective even as new variants emerge.”

The research was largely funded by UK Research & Innovation, the European Association for the Study of the Liver, the NIHR Cambridge Biomedical Research Centre and the Evelyn Trust.