The race to find treatments and other therapeutic options such as vaccines for COVID-19 is on, and success is still a long way off - at least not before the start of 2021, according to Stuart Ralston, professor of rheumatology at the Centre for Genomic and Experimental Medicine, University of Edinburgh. He is also chairman of the Commission on Human Medicines (CHM) at the Medicines and Healthcare Regulatory Authority (MHRA). On Thursday he took part in a Royal Society of Medicine Webinar to discuss the potential treatment options for the COVID-19 virus. He discussed the evidence surrounding the drugs and other therapies proposed as treatment options for COVID-19; drug-related concerns around coronavirus, and the randomised clinical trials that are currently underway. He was in conversation with Professor Sir Michael Rawlins, chairman of the MHRA. Prof Rawlins is a clinical pharmacologist and specialist in internal medicine.
Sir Michael asked what role the CHM had during the pandemic? Prof Ralston was keen to point out that the CHM had been working very hard to try and deal with the pandemic and that they have been able to fast track applications for new clinical trials and new drugs that might be useful in the condition. He went on to say that "the priority of the MHRA and the CHM is to make sure your medicines are safe, we are not cutting corners, by no means, but if we think that it is possible to take steps to review a clinical trial application or get a medicines licence in the quickest way we possibly can, then, that's what we're going to do".
NSAIDs and COVID-19
Asked whether using drugs such as ibuprofen for symptomatic patients could be useful, Prof Ralston responded that following collaboration with the National Institute for Health and Clinical Excellence (NICE), a systematic review showed no evidence that ibuprofen would worsen the severity of COVID-19 or make people more susceptible to COVID-19. His advice was that it can be safely taken if necessary, and if a patient has already been prescribed ibuprofen for any condition they should continue to take it.
Angiotensin Converting Enzyme Inhibitors (ACEIs) Angiotensin Receptor Blockers (ARBs) and COVID-19
Sir Michael asked next about the suggestion that people who were taking ACEIs or ARBs might be at greater risk of either developing COVID-19 or having more severe symptoms. Prof Ralston was keen to highlight the fact that large observational clinical studies had shown no association between ACEIs or ARBs and severity of COVID-19. This suggestion was unfounded, he said, and he urged those patients who had already been prescribed these drugs for hypertension or heart failure to continue to take them.
Prof Ralston discussed the CHMs involvement with the authorisation of vaccine trials, and specifically talked about the Oxford vaccine trial. In April, University of Oxford researchers began testing a COVID-19 vaccine in 1110 human volunteers in Oxford. He described the vaccine as a deoxyribonucleic acid (DNA) vaccine using an adenovirus-based vector, and said that there were other types of vaccines at the clinical trials stage, including an RNA-based vaccine in the US. The US Biotech Company Moderna, based in Cambridge, Massachusetts, has received Food and Drug Administration (FDA) Fast Track designation for their mRNA vaccine candidate (mRNA-1273) against novel coronavirus. They are finalising a protocol for a phase 3 study of mRNA-1273, which is expected to begin in early summer 2020.
Chloroquine and Hydroxychloroquine
Prof Ralston described the French study highlighted recently by President Trump as a "very poor study, which was poorly defined, that you couldn’t make anything of". He said there was "no evidence that chloroquine or hydroxychloroquine is effective against COVID-19. However, it is one of the drugs that is also being studied in the University of Oxford RECOVERY Trial (Randomised Evaluation of COVID-19 Therapy). This study has enrolled 12,000 patients and it is anticipated will be complete by June 2021.
Azithromycin was not considered to be efficacious against COVID-19 as it isn’t an antiviral, but Prof Ralston said it may have "some use in those patients who may subsequently develop a post-recovery bacterial infection". However he didn't think it should be prescribed off-label.
Prof Ralston described remdesivir as an anti-viral drug originally developed for Ebola that inhibits RNA polymerase. He considered there to be a good biological basis for its use in treating COVID-19, but referred to the recent Lancet study which he said "showed small benefit in terms of hospital admission, but certainly no benefit in terms of mortality". However, in spite of this caution, the BBC has said that US pharmaceutical giant Gilead and five generic pharmaceutical companies (Cipla Limited, Ferozsons Laboratories, Hetero Labs Ltd, Jubilant Lifesciences and Mylan) in India and Pakistan have signed an agreement to expand supply of the drug for treating COVID-19.
Prof Ralston said that because of its known use in HIV, remdesivir might have some use in COVID-19 as it is a protease inhibitor. However he went on to add that "it hasn’t been designed to target the COVID-19 proteases, so it's possible it may not work". He added the caveat that he thought perhaps it was because remdesivir was available "that's the reason why they've been entered into clinical trials". Prof Ralston admitted that remdesivir was "certainly a drug that shows some promise but we don't know if it is effective yet".
Steroids and Immunosuppressive Agents
"Paradoxically," he said, "on the one hand these drugs might make you more open to infection, yet they are being used to treat it. The rationale for use stems from the fact that in patients who are severely affected by COVID-19 they do seem to get this cytokine storm, a very severe lung disease with a lot of cytokines being produced, and we know that these drugs can be helpful in that situation." He cautioned against the use of such drugs in patients in the early stages of COVID-19 who were only mildly symptomatic.
Professor Ralston said that inhaled interferon was initially being trialled in the Oxford Recovery Trials but had to be halted because of difficulties getting the product for their trial. However, UK based company Synairgen plc has received expedited approvals from the MHRA and Health Research Authority (HRA) to conduct a trial of inhaled interferon via a nebuliser versus placebo in COVID-19 patients.
Other Therapeutic Options in the Fight Against COVID-19
The term 'convalescent plasma' has been around in the scientific community for quite some time, but has re-emerged in the fight against COVID-19 as the scientific community examines its uses. The theory is that if someone is convalescing from COVID-19, they will have antibodies to the virus in their serum. Prof Ralston said: "that might help as a therapeutic, and is being trialled at quite an early stage. The National Blood Transfusion Service have been very much involved in sourcing the material, and donors who have had COVID-19 are very kindly helping to donate, so it's an interesting therapeutic approach."
He added some clarity about why the plasma of people recovering from COVID-19 might help. "The evidence suggests if you've had a severe infection you have a more marked immune response and therefore produce more antibodies. People with more severe infection seem to make more antibodies, and theoretically it might be better to use their plasma, but who knows? As I say, we don't really know what it is that works." Prof Ralston drew listeners' attention to the fact that it was not only antibodies that were important but also B- and T-cell-mediated immunity.
Therapeutics for COVID-19 in Children
Prof Ralston touched on the new information coming out about COVID-19 type illnesses in children and the similarities to another type of vasculitis called Kawasaki disease. Sir Michael specifically asked Prof Ralston whether we needed to do separate clinical trials for children with COVID-19, or could we adapt information about dosage in adults and adjust those findings for children, depending on their weight? Prof Ralston said: "It would be better to wait for the results of the trials, but of course in the UK if paediatricians feel a treatment, maybe steroids or whatever, is likely to be beneficial, they can use that treatment in individual patients. That would depend very much on the experience and the clinical judgement of the paediatrician in charge."
Sir Michael asked Prof Ralston whether vitamin D was useful in the fight against COVID-19. Prof Ralston said that COVID-19 was more severe in older people and the BAME (black and minority ethic) group of people, in both of whom vitamin D deficiency is common. However, low levels of vitamin D could occur in practically every illness, he said. "What happens is, if you're ill, you don't get out, you might not be eating so well and vitamin D levels fall." He said there was no current evidence to suggest that vitamin D supplementation would prevent COVID-19 or reduce its severity. "However," he added, "that could be an area worthwhile looking at in a clinical trial. It certainly would not be difficult to do to make it widely available, it has a good therapeutic margin." Even so, he "certainly wouldn't advise people to take vitamin D to prevent COVID-19 or treat COVID-19". However, adults in BAME groups in the UK are already advised to take 10 microgram vitamin D supplements throughout the year, and everyone is advised to take them between October and March, when British sunlight is not strong enough to provoke skin manufacture.
The BMJ has said there is "a deluge of poor quality research which is sabotaging an effective evidence-based response to COVID-19" and a report in the Lancet entitled "Flooded by the torrent: the COVID-19 drug pipeline" has echoed this. It seems Prof Ralston agrees with the sentiments. He said: "There are so many trials and so many drugs for COVID-19 it's really difficult to keep pace."