Biologic therapies for severe asthma with persistent type 2 inflammation

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Hello and welcome to the Australian Prescriber Podcast. I'm Jo Cheah, a hospital pharmacist in Melbourne and your host for this episode. It is a pleasure to be speaking to Professor Peter Wark. Peter is a Professor of Medicine at Monash University in Clayton, Victoria. Welcome Peter.

Thank you very much, Jo.

So Peter, you and your co-author, Sahan Chandrasekara, have written an article about biological therapies for severe asthma in Australian Prescriber. To start off today, can you explain severe asthma and how this differs from difficult asthma?

People with severe asthma make up a relatively small proportion of the overall population with asthma. It's estimated to be around about 5 to 10% in total. But that 5 to 10%, while they're a small proportion of the overall people with asthma, they really have and suffer with the highest burden of illness. So they're individuals in whom you can't control the disease despite treatment with high-dose inhaled corticosteroids or a long-acting beta agonist controller together with them. So really while they're small in number, they really do represent a very important group.

So that's the definition of severe asthma. Now, difficult asthma sounds very, very similar, so difficult asthma is anybody who doesn't achieve control with inhaled [corticosteroid] therapy and has ongoing symptoms or a need to use prednisone [oral corticosteroid]. But most common reasons for this are that people aren't taking the medications as prescribed, are uncertain as to how to use the devices that they have, or have lapsed in the use of their device for some other reason. It's a subtle difference, but it's an important one.

Biological therapies are only indicated for patients with severe asthma and persistent type 2 inflammation. Can you please define persistent type 2 inflammation? Are there any markers to test for this, and are those sorts of tests available through the GP?

They absolutely are, Jo. So when I talk about type 2 airway inflammation, I'm talking about this inflammation which is associated with allergy and eosinophilia, and this is related to mediators like interleukin-5, interleukin-4 (IL-4), and interleukin-13 (IL-13) that circulate around in the blood and have effects on the airway, that worsen the inflammation, cause the thickening of smooth muscle and the twitchiness that we describe in asthma. So, asthma needs to be diagnosed by measuring lung function and showing that there is variability in airflow obstruction and that needs to be done on spirometry. Once you have that diagnosis, you need to go looking for evidence of this type 2 inflammation.

Now in fairness, if you've got someone with symptoms and you've demonstrated that they have variable airflow obstruction, they are very, very likely to have had, or have evidence of, type 2 airway inflammation anyway. So you just start them on low-dose inhaled [cortico]steroid. That's perfectly fine. It would be reasonable also to step up to a medium-dose inhaled corticosteroid together with a long-acting beta agonist if they're not getting control with those symptoms. But once you're there and people are taking their inhaled medications but are still having symptoms or have had a history of an exacerbation, then you need to look for presence of inflammation which is not being controlled by these low-, medium- or high-dose inhaled [cortico]steroids. So how do we do that? Well, we've got 2 tests.

The simplest one and the one that's available for all of us is to look at the blood eosinophil count. This correlates pretty closely to the presence of these eosinophils in the airways as well. So, a level of blood eosinophils of greater than 0.3 × 10⁹ [cells/L] or 300 cells/microlitre, in the context of asthma that is not being controlled by moderate- to high-dose inhaled corticosteroid and a long-acting beta agonist, tells you that there is ongoing eosinophilic airway inflammation. And that is persistent type 2 inflammation despite your standard anti-inflammatory treatment.

Now there is a second test which can be measured. Largely in Australia, this can only be done in lung functional laboratories. It's done at the same time as spirometry. And this test is called FeNO for short, which stands for fractional exhaled nitric oxide. This is usually elevated together with eosinophils being elevated, but not always. It reflects the action of the chemical mediators IL-4 and IL-13 directly on the airways. It's measured as a point-of-care test. It's very sensitive to inhaled corticosteroids, so it will go down if you're using inhaled corticosteroids and your inflammation can be controlled. But again, where that is not being suppressed by a reasonable dose of inhaled [cortico]steroid, then you've got inflammation which is not responding to your standard treatments.

So, we've now got 2 tests that are readily available that will tell you whether there is still inflammation going on in their airways. So, what would this look like with the patient in front of you?

You've got a patient, you know they've got asthma, they've previously demonstrated that they've got variable airflow obstruction, you've got them on treatment with an inhaled corticosteroid, long-acting beta agonist, and they're still having symptoms, poor disease control day-to-day or a history of exacerbations that have required treatment with prednisone. And you open up your medical record and you have a look at what their blood eosinophil count is and you can see that it's greater than 0.3 [× 10⁹cells/L]. This would indicate a person who's going to benefit from a biologic agent. And those biologic agents will control that persistent type 2 inflammation.

That's really clear. Thanks Peter. So, as you were saying what this would look like in a clinical picture, you've got the patient in front of you, you've got the red flags. Would you expect the GP then to refer this patient to a specialist to commence or consider biological therapies?

That's exactly right, Jo. At this point in time, the PBS requirements are that you need to be seen by a specialist, either a specialist in asthma and respiratory medicine, or immunology, or a paediatrician in the case of children over the age of 6 [years], to access biologics. There is absolutely no reason that people should be suffering with long-term courses and frequent courses of prednisone now. These [biologic] agents really should now be preventing the need for people to use regular prednisone. That just shouldn't be happening.

Other treatments are not proven to be helpful. So, if you are already on a high-dose inhaled [cortico]steroid, adding in montelukast is generally unhelpful. If someone has got fixed airways disease still and symptoms, so their FEV₁ [forced expiratory volume in 1 second] is less than 80% predicted and they're complaining of breathlessness, they might benefit from the addition of a long-acting [anti]muscarinic agent. But if they've got this persistent type 2 inflammation, if they've got poor control, particularly with a history of exacerbations, the flag's up, they really need a biologic.

And what are the available biologics at the moment and the main differences between them?

So we've got 4 now that are available. The one that's been around for longest is omalizumab. It's a biologic agent that targets IgE [immunoglobulin E]. So that's the antibody that goes up in allergy and allergic disease. And for that reason, this treatment is also helpful in urticaria and, very recently, probably helpful in serious IgE-mediated food allergies. And this monoclonal antibody binds to the IgE that is circulating around in the bloodstream and prevents the cross-linking of those antibodies on mast cells and the release of inflammatory mediators like histamine that cause more inflammation in the lungs. It's suitable for use in people with severe asthma with evidence of allergy either with an elevated total IgE, or skin prick test positive or RAST positive.

The other agents, there are 2 that target interleukin-5 and that allows for recruitment of eosinophils from the blood to the airways. These 2 agents are mepolizumab and benralizumab. They do work slightly differently, but really what they do is block the effect of interleukin-5. That stops eosinophils from entering the airways and they have been shown in people who have severe asthma and persistent eosinophilia to improve symptom control and reduce the risk of exacerbations. You do not have to have allergy to benefit from mepolizumab or benralizumab.

And, finally, we have dupilumab. Dupilumab targets interleukin-4 and interleukin-13, and that's obviously involved in allergic disease. It does work by preventing the action of these chemical mediators. And when you give this medication in people with severe asthma, the first thing you see is that their [fractional] exhaled nitric oxide should go down and easily go back down to normal limits. It takes longer to have an effect on other aspects of allergy and eosinophilic inflammation, and sometimes that can actually go up temporarily, but it controls that inflammation and, similar to the other agents in people with severe asthma, has led to very substantial improvements in terms of reduction of exacerbations and better control.

There's no head-to-head comparisons at this stage between the 4 agents. They each do have some subtle differences. Dupilumab is accessible for people who have severe asthma and allergy and/or elevated blood eosinophils. Mepolizumab, benralizumab, only for people with elevated blood eosinophils but you don't have to have allergy. And omalizumab, you have to have severe asthma and allergy.

Very clear again. Thanks Peter. How are these biologics administered and can patients self-administer them at home?

All of these biologics have to be administered through a subcutaneous injection, but they are provided with devices that are either very easy to use, that can be self-activated, or a prefilled syringe. So omalizumab and dupilumab have prefilled syringes that are relatively easy to operate, very similar to what you would see with insulin. Both mepolizumab and benralizumab have a prefilled device, which is even easier to use rather than just the prefilled syringe.

What are the side effects of biologics and are there any long-term risks with these therapies?

The side effect profile is very favourable with these agents overall. A lot of GPs out there will have now been experienced and exposed to a lot of biologic agents, and most of them target aspects of the immune system, particularly biologics used for rheumatoid arthritis and inflammatory bowel disease. And those agents do tend to be quite immunosuppressive. These biologics target allergic inflammation, not the other types of inflammation that we really rely upon to fight off infection. And while there've been some theoretical risks that you might see certain types of parasitic infections, which we rarely see in Australia except perhaps for far northern Australia, that really hasn't carried through. And so there isn't really a heightened risk of infection that's been clearly demonstrated with any of these agents.

You can get some local reactions of irritation of the skin. Very, very rarely you can get allergic reactions to these agents. It's possible you may in a very small number of people build up some resistance to them working, but that doesn't cause side effects. It just may reduce their efficacy, although that's a little unclear at the moment.

And, of course, the important thing to remember is that the alternative is that they're exposed to frequent if not regular courses of oral corticosteroids such as prednisone. And oral corticosteroid processes accumulate throughout life. They increase for risk of serious comorbidities, particularly cataracts, osteoporosis. They increase the risk of infections such as pneumonia, and they have an adverse effect on cholesterol, other features of metabolic disease and cardiovascular disease as well. So, the risk–benefit profile for these biologics is incredibly favourable.

In terms of long-term side effects, omalizumab has now been in use for approximately 15 years. There have been no clear associations with any long-term side effects. The other agents have not been around for as long. And again, there are no clear associations with long-term side effects.

And what is the current consensus for the duration of treatment with biologics in this indication?

The majority of people who go onto a biologic agent are unlikely to come off them. But at this stage it's not clear, and in fact in the majority of people it’s almost certainly the case that, once you withdraw these agents, their asthma tends to come back again.

We need to do work to define whether there's groups of people in whom we can induce what we call lasting remission, but we really don't know that at the moment. So at this stage, I'd have to say that's a long-term treatment and most patients will then stay on a biologic agent to control their disease.

My last question for you, Peter, is should patients continue to receive corticosteroid inhaler therapy whilst being treated with a biologic?

The short answer is yes, they are still going to require treatment with inhaled therapy as well, but we can often reduce that burden of treatment that they're on. And it's probably best to do that in a stepped way. For the majority of patients, I think the aim would be to get them at least onto low- to medium-dose inhaled [cortico]steroid [with a] long-acting beta agonist.

Thank you, Peter. That brings us to the end of the episode. Really appreciate your time and for coming onto the program.

It's a pleasure, Jo, and thank you very much.

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Peter and Sahan's full article is available on the Australian Prescriber website. The views of the host and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. I'm Jo Cheah, and thanks again for joining us on the Australian Prescriber Podcast.

Peter Wark has received funding for an investigator-initiated trial from GlaxoSmithKline to compare effectiveness of omalizumab and mepolizumab in severe asthma. He has received honoraria to speak about severe asthma from AstraZeneca, Sanofi, Regeneron, GlaxoSmithKline and Novartis.