Interferon Beta Inhalation Shows Promise in Treating COVID-19

John Whyte, MD; Stephen Holgate, MD


December 14, 2021

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JOHN WHYTE: Welcome, everyone. I'm Dr. John Whyte, the chief medical officer at WebMD, and you're watching Coronavirus in Context.

We know that vaccines alone are not going to quash this pandemic. We also need to have therapeutics, treatments. We've been talking a bit about them over the past few weeks. Most of them are in the form of pills as antivirals.

But there's also been some discussion about a drug that can be inhaled by the lungs. So joining me to discuss the latest data is Dr. Stephen Holgate. He's the Medical Research Council clinical professor of pharmacology and honorary consultant physician within medicine at the University of Southampton. He's also one of the founders of Synairgen, a university spin-off and public limited company working in drug discovery and biotechnology. Dr. Holgate, thanks for joining me.


JOHN WHYTE: Actually, it seems I should be referring to you as Sir Stephen Holgate, shouldn't I? Because I want to point out to our viewers: We tried to get you on earlier, and you couldn't participate because you were being knighted by the queen. I get a lot of excuses, but never like that.

STEPHEN HOLGATE: Well, yes. And it was a very nice day at Windsor Castle. Thank you.

JOHN WHYTE: What was that like?

STEPHEN HOLGATE: I mean, because of COVID, they did it differently than usual. So they did it one at a time. I was first in line with my wife. So we entered the room, had the national anthem with a lovely quintet playing the music, and Princess Anne, the princess royal, was the person who actually got the sword out.

I was a bit nervous at the time what she was going to do with that. But I was told to kneel down, as I did, and she touched me on each shoulder. So that was very nice. And we a nice chat afterwards.

JOHN WHYTE: Well, congratulations. What an honor and recognition for your work. And I want to spend a few minutes about your work. You've mostly spent it in the area of respiratory diseases -- asthma and COPD. What made you think about how can you apply what you learned from these conditions to COVID?

STEPHEN HOLGATE: Well, we got interested in viruses and respiratory tract because many of the severe diseases are made worse in the lung, with infections. And I had the great privilege of working with the man who discovered coronavirus, first of all, back in the early 1960s -- the Common Cold Unit in Salisbury.

So it was a natural link, really, when we started to see coronavirus reappearing, not this time causing common colds but something much more serious, which, of course, we all know about now. But that's how we really got involved in it.

JOHN WHYTE: Let's talk about the role of interferon beta. What role does that play in our immune system?

STEPHEN HOLGATE: Well, we have two parts of our immune system, as most of the listeners will know. We have something that defends us when an infectious agent first enters into the human body, and we call it the innate immune system. And then we have a second wave of protection that takes a few days to develop, called the adaptive immune system or acquired immune system. And these are the antibodies and the lymphocytes and all the other parts of the very specific, directed immune system.

The innate immune system is non-directed. In other words, it's many hundreds of genes being switched on, which give us the antiviral defense.

JOHN WHYTE: How does coronavirus turn off these processes?

STEPHEN HOLGATE: Well, this was the fascinating part of the story, really. We'd already done some work, earlier on, in asthma and COPD showing that by giving interferon, we could actually reduce virus-induced exacerbations. And of course, when this came along, we started to look at this virus.

And it seemed that it had changes in its structure that made it able to evade this innate immune system, to evade the production of interferon beta. And in addition, as has turned out now, over the last 6 months to 2 years, we found that there are human beings who have genetic abnormalities in the pathway as well. And finally, we've learned very recently that antibodies are made against other interferons -- not interferon beta, but interferon omega and interferon alpha, which help to neutralize their effect. So these are the three reasons, really, why we felt interferon beta might be special here.

JOHN WHYTE: Well, let's talk about the studies that you've done and you're currently working on. Bring us up to speed on what you've found so far.

STEPHEN HOLGATE: Well, initially, of course, we had shown that interferon beta could neutralize various viruses in in vitro cultures, as others have shown. But what we were able to do is set up a phase II clinical trial in COVID-19. And this was 101 patients -- half treated with placebo, half treated with inhaled interferon beta given once daily for 14 days on patients who are hospitalized with COVID-19. So they had to cross the threshold, clinically, to be admitted to hospital.

And then we followed them for 28 days until after they were discharged from hospital. And the results were really quite surprising to me because we'd already had experience with inhaled interferon beta in asthma, COPD, and we did get responses. But the responses on this were really quite extraordinary.

We were able to show that patients were able to return to full recovery much faster when they had the active rather than the placebo treatment. We were able to show, on the World Health Organization scale, that there was a rapid improvement in their ability to be able to function. And finally, just taking one symptom -- shortness of breath -- we were able to show highly significant differences between the active and the placebo on that particular symptom, which is a very dominant one in COVID-19.

So this is all very encouraging. But of course, it's a phase II trial, and we have to go further if we were going to explore it into a clinical domain.

JOHN WHYTE: Now, what's the role of this being an inhaled therapeutic? Mostly, when we talk about antivirals, they're either pills, as we recently have seen, or they're infusions, or an IV has to be inserted into your vein. This is something that could be done as a nebulizer treatment. Does that play a more important role? What's the current thinking?

STEPHEN HOLGATE: So we have to think about the pathology and the processes going on in the human when somebody is infected with this nasty virus. And obviously, the lung is the battleground that begins the whole process. The lining cells of the nose, and then the airways, and finally the alveoli -- the type II pneumocytes, we call -- become occupied by this virus. And in essence, this virus utilizes the cellular reproductive machinery to reproduce itself.

So if we're going to really gain the benefits of the innate immune response, we don't want lots of this protective agent circulating in the blood or going to the brain or going anywhere else. We want it where the action is. And the action is in the lung.

So giving it by inhalation, we can get very high concentrations of the agent in the lung with very low concentrations in the circulation, which is what we want. Whereas, if you gave it systemically, which is what has been tried in clinical trials, it has relatively little effect, because, obviously, you need massive doses to be able to get the drug, the interferon beta, to go in a reverse direction and to reach the surface of the lung where all the action is happening.

JOHN WHYTE: But how will that address issues such as vascular complications of COVID? Some of the thrombotic issues that we're starting to see -- will it still have an impact there?

STEPHEN HOLGATE: Well, I think a lot of the cyanosis and breathlessness of the COVID-19 illness is caused by the microvascular disruption. And of course, these are the small blood vessels right underneath the alveoli, where we can see leakage and small microthrombi developing. And if they're getting inhaled interferon beta and it penetrates across a damaged epithelium, it'll reach these small blood vessels. And they have the ACE2 receptor as well, and they're the ones infected, in parallel with the epithelial cells.

So again, this is local treatment. This is not giving treatment into the bloodstream looking at its effect systemically, but we're trying, now, to block the cascade which happens when the cytokine storm begins by attacking the place where the virus is most active.

JOHN WHYTE: As I mentioned, you've been involved in respiratory diseases much of your career. What, if anything, has surprised you about COVID-19?

STEPHEN HOLGATE: Well, the respiratory viruses are all around us. And of course, most of an average respiratory physician's work is around coping with the effects of infections of one form or another.

But this was different. This was totally different. Here, we were dealing with a disease that really took people's lives away at a remarkably rapid pace. And the symptomatology was very different. And you've already mentioned one of them, the changes to the blood clotting, which is highly unusual with infections.

But also, there are other features that are unusual, such as the selective picking off of the olfactory epithelium, which has got something like 15 to 20 times as higher concentration of ACE2 receptor. So killing nose epithelial cells leads to the loss of taste and smell, which is another very characteristic feature.

And then I mentioned breathlessness. Well, obviously, multiple causes of that. The microvascular bit is important. But probably more important, to some extent, is the edema and thickening and the damage to the alveoli when the virus starts to cause the damage to the type II pneumocytes. And of course, that leads then to the cascade of events, which leads to hospital admission.

JOHN WHYTE: I want you to put it in perspective for us. Is this the toughest challenge that you've faced over your career? Or has there been other diseases that, in some ways, have been more complicated, more difficult to address?

STEPHEN HOLGATE: I think this has been one of the most interesting diseases because a single cause, one single virus type, has led to all of this incredible pandemic across the world, whereas most of the diseases that I've been involved with -- such as asthma, COPD, and maybe fibrosing alveolitis, interstitial coronary fibrosis -- seem to be much more complicated in the environmental factors that drive them.

But here, are we dealing with one environmental factor: a virus which is breathed in, which is causing this massively complex and severe disease. So in a way, it's a big challenge. But on the other hand, it gives us a handle on a disease, where some therapeutic -- and we're saying interferon beta, in this case -- would have a potentially very major effect.

JOHN WHYTE: Well, Dr. Holgate, I want to thank you for taking the time today. We're going to speak with your colleague Richard Marsden later in the week to find out more about when this might be available to the general population.

And congratulations again. What an amazing honor to be knighted by the queen. We all have to express our appreciation to what you've done in the field of medical research over the past few decades.

STEPHEN HOLGATE: Thank you very much. Most kind.

This interview originally appeared on WebMD on December 13, 2021

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