Putting the brakes on COVID-19: an interview with Sir Marc Feldmann

Putting the brakes on COVID-19

An Interview with Professor Sir Marc Feldmann

COVID-19 is, by all accounts, a once-in-a-lifetime pandemic. Fortunately, our senior medical Fellows like Marc Feldmann have been coordinating a oncein-a-lifetime response to the crisis, including new clinical trials, advice and research partnerships.

Abrief read of our Somervillians Stepping Up feature (p.29) is enough to confirm that there is hardly an institution or place of work where Somervillians have not been making a positive impact since the pandemic began. In this feature, however, we have taken the opportunity to focus on the profound contribution made by our senior medical Fellows to the global fight against COVID-19, including an in-depth interview with Sir Marc Feldmann, winner of the 2020 Tang Prize for Biopharmaceutical Science.

In this interview, Sir Marc takes us through how anti-TNF therapy works and why it is being tested as a coronavirus treatment, the difficult process of running clinical trials in the middle of a pandemic and how soon life might go back to normal.

First things first, can you possibly explain in layman’s terms how anti-TNF works? Well, if you picture inflammation as a little car race, you’ve got six cars all racing each other to deliver the inflammation. Now, our theory was that if you took just one car out of that race – in this case, the cell-signalling protein or cytokine known as TNF – then the inflammation would stop. At the time most people thought this was crazy because they assumed – quite reasonably – that the other five cars were still there, doing their thing, and inflammation would ensue. However, we had evidence that suggested removing TNF slowed the other cars down. It was very unexpected, but that’s the point about science: often you have data that changes how you think about

everything, after which it’s your job to figure out why it works that way. You always have to follow the science.

And how did you decide anti-TNF could be effective against COVID-19? It comes down to evolution. Every cell in our body has the same 20,000 genes strung out in their chromosomes within the nucleus. In some cells, certain genes are activated to do what that cell does, and in another cell it’s a different gene. Now, replicating all this information every time a cell divides is quite a burden, so there is a very important evolutionary principle that you don’t keep genetic instructions that have no use.

The upshot of this is that, in many different diseases, things are often done exactly the same way. That is why more than 10 diseases are approved for anti-TNF, with almost as many more responding that are still unapproved. So when a new disease like COVID-19 comes along, it makes sense to ask whether it’s using the same pathway as existing related diseases. Blood tests of COVID patients confirmed that TNF was abundantly produced, while a new tool called bioinformatics, which analyses databases of computerised records, confirmed that inflammatory bowel disease patients using anti-TNF had very good outcomes from COVID-19.

Having established the justification for a trial, what was the next stage? Well, the most difficult part of any trial is convincing people your trial is worth pursuing. This was especially true with COVID-19, because it was a new disease, and there was a lot of pressure from various parts of the government to get something done and a lot of money allocated to UK R&I. So my role in these initial stages was alerting people that anti-TNF hadn’t been considered and then convincing them that a trial was necessary. That’s where the data I just mentioned came in: we used it to co-author a rationale that was published in The Lancet in early April, with further support coming in May following reports of improved outcomes for rheumatological patients on anti-TNF.

You always have to follow the science.

ADAPTING ESSENTIAL CARE: PROFESSOR RAJESH THAKKER

Within a few days of lockdown, Somerville’s Professorial Fellow and May Professor of Medicine, Rajesh Thakker was asked to contribute to a COVID-19 response report by the Royal College of Physicians. Acting in his capacity as President of the Society for Endocrinology, Professor Thakker solicited responses from 27 senior academic and clinical endocrinologists. The combined feedback was translated into a report on the effects of COVID-19 on current clinical services and activities, and how the various branches of medicine propose to deliver patient care, teaching and research in the future. Professor Thakker has also co-authored an article on the management of neuroendocrine tumours during the COVID-19 pandemic to establish the critical emergency investigations and treatment. The report was published in the European Journal of Endocrinology in June 2020. Finally, Professor Thakker provided advice and input to two patient groups (AMEND, for which he is patron, and ParathyroidUK) for their Frequently Asked Questions in regards to the pandemic.

We [will] have an equilibrium where people are more conscious of how to behave and protect others

Once you persuaded people of the need for a trial, I guess the next stage was to design it? Pretty much, although in this case there are actually two trials – one to evaluate the effectiveness of anti-TNF at the beginning of the disease, and one when the disease is more advanced. We’ve actually started with the second of those trials because it is important to get results quickly with a deadly disease like this, and the best place to do that is the hospitals.

Our hope with the hospital trial is that anti-TNF will stop patients experiencing respiratory issues and needing oxygen, so they don’t progress to intensive care, where they face a much higher mortality risk. Huge credit must go here to Professor Duncan Richards of the Oxford Clinical Trial Unit for designing the trial at the practical and regulatory level, because there are many, many steps to negotiate between the initial concept and getting it done safely.

NUCLEIC ACID THERAPY AGAINST COVID-19: PROFESSOR MATTHEW WOOD

Matthew Wood, who is Deputy Head of the Medical Sciences Division, Professor of Neuroscience and a Somerville Professorial Fellow, is also the founder and interim executive director of the recently established UK Nucleic Acid Therapy Accelerator (NATA), based on the Harwell Campus south of Oxford. Over the course of March/April 2020, Matthew is leading an international research consortium comprising investigators from NATA, Oxford, The Crick Institute, clinical centres in Germany and Italy, and a commercial partner based in Boston USA, with the goal of developing the first oligonucleotide drug therapy for Covid-19 and evaluating this in a first-in-man clinical trial within 12 months. Uniquely, oligonucleotide drug design developed by Oxford/NATA will be fine-tuned based on SARS-CoV-2 RNA structure data emerging from The Crick Institute. The team has received significant funding for this work from UKRI, and the project, while at an early stage, is on track to meet its goals. And what about the second trial? If you think about the coronavirus epidemic, it has two big problems. The first problem is the disease itself and its impact on individuals, both in terms of mortality and long-term health issues. The second problem is that this is an economic disaster, and the economic disaster comes in several flavours: people are no longer working, those working in public-facing roles will find it difficult to carry out their work, there are serious ramifications for mental health and, of course, with the hospitals converted to COVID-wards, all our other diseases have been badly treated for the past several months. So you could actually argue that the knock-on mortality of other disease treatment being deferred is actually going to have a more profound impact than COVID-19 itself.

That’s what the second trial is about. Its main objective is to keep people out of hospital, because if you keep people out of hospital you relieve the medical issue, but you also address the socio-economic issue. You could ask, why aren’t we doing this trial first, as it’s clearly very important to keep people out of hospital and rescue the economy. The answer is that this type of trial is much harder to organise and run. Fortunately, Duncan Richards came up with a good way for us to conduct this trial outside the hospital environment. He found a very useful organisation called Hospital at Home, who send out hospital consultants to visit patients at home, and they’re kitted out with all the equipment to make a diagnosis and initiate treatment.

You also have a role with the SET-C, providing COVID advice to the government. Can you tell me a bit more about that and how the SET-C differs from SAGE? SAGE actually has a very difficult job to do because it is so multi-disciplinary, which means that much of the time you are experts discussing topics about which you have no direct knowledge. The SET-C (Science in Emergencies Tasking – COVID) was set up by the Royal Society to support SAGE by ensuring that they and others have access to the right information in emergencies like this.

THE SPIKE TRIALS: PROFESSOR DANIEL ANTHONY ET AL

The SPIKE trials were conceived by Dr Bobojon Nazarov (2011, MSc Pharmacology) in March 2020, following his observation that existing studies had shown two proven drugs, Nafamostat and Camostat, to block the entry of coronavirus into lung cells. Dr Nazarov partnered with three other Somervillians, Professor Daniel Anthony, Dr Emma Ladd (2007, Medicine) and Dr Suzie Anthony, as well as researchers from the universities of Oxford and Edinburgh, to see if these drugs might save lives while a vaccine is developed. The first trial, for which Professor Anthony is acting as Scientific Lead, will seek to evaluate the effectiveness of Nafamostat in preventing clinical progression of the disease. The second and larger of the two trials, for which the four are co-investigators, is being sponsored by Cancer Research UK with support from medical research charity LifeArc, and will evaluate whether the pancreatitis drug Camostat could also limit progression of the virus.

find out who does through the academic networks at our disposal, and we can co-opt more experts as needs evolve. We also ensure our guidance remains clear and accessible by limiting how much literature we produce and always publishing our guidance on the Royal Society website a week after Government receives it, and in scientific journals where appropriate.

Pulling back a little, how do you think the world will look in six months’ times. Will we have a vaccine? I think the vaccine issue is important, because life won’t get back to normal until there are to have a vaccine in six months’ time; most experts agree 2021 is more likely. That’s not to say it’s impossible – unprecedented things can happen. However, I think it will be more likely that, come December, we have an equilibrium where people are more conscious of how to behave and protect others. Masks will have a significant role to play there, I think – the advice from the Royal Society, much of which was formulated by Professor Melinda Mills here in Oxford, has been very clear on that. Of course, there is a cultural issue to negotiate here, which is that the British public are not used to wearing masks and the British government is no longer in a strong position, following its treatment of Mr Cummings, to tell us we’re all in this together, so let’s all wear masks. However, this doesn’t change the fact that those countries which have experienced SARS and these types of outbreaks in the past have done really well with COVID-19 because

vaccines. But it would be unprecedented they are used to wearing masks. Taiwan, for example, didn’t have a lockdown, but it did have a very well-observed practice of maskusage, resulting in a total of 7 deaths for a population of 24 million.

So that is the position I am encouraging Somerville to adopt: for indoor communal spaces, wearing masks should be routine. In a small community like Somerville, where you’ve got a lot of switched-on people, compliance with that will be around 98%, with the other 2% of people not complying simply because they left their masks at home. But wearing a mask outdoors when there is a risk of meeting people outdoors as done in Taiwan is a good idea. That’s what I do.