Andrew White, MD

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: 

We talked about biomarkers to start this conversation and segment, to qualify the level of severity of asthma. And we’re going to wind down now and come full circle. Dr Siri, what is the role of biomarkers as you progress prognostically and follow your patients who are on biologics?

: Thank you for asking me that because we’ve all been throwing out the word biomarkers without actually really defining them. The FDA defines biomarkers as something that we can objectively measure that really will give us a prediction in terms of health, disease, perhaps treatment response to a therapeutic, or even just an exposure. Specific to moderate and severe asthma, one of the big biomarkers we’re talking about is the eosinophil count, which is easily measured in a primary care office…. So thank you for doing a great job and getting a CBC [complete blood count] with differential before you refer them. We would love that. An eosinophil count greater than 150 [cells/µL] certainly can be indicative of type 2 inflammation. That is helpful, and that’s been borne out by some clinical studies that we talked about. And a count of 300 or greater has additional prognostic markers.

Fractional exhaled nitric oxide [FeNO] is also really important in terms of that correlation. FeNO may not be as available for a primary care audience, but certainly, for allergist immunologists, we measure it very frequently. And this could be indicative of airway inflammation and certainly interleukin-13 activity. Someone with a FeNO level of 20 or 25 ppb or greater is considered inflamed and could benefit from additional treatment.

You can think of that also in other pulmonary function testing such as spirometry. We can use FEV1 [forced expiratory volume in first second of expiration] as a measure. Also, impulse allometry, which is making a comeback, can be used as a measurement in terms of increased risk.

When we use biomarkers, we can also think about immunoglobulin…or some of the other blood work that we might check. Those don’t have as much of a predictive outcome as eosinophils and FeNO, but they certainly still would be helpful. Lastly, there may be something such as genetic biomarkers. This is becoming more and more advanced as time goes on. And I think at some point we will be able to direct treatment in terms of those genetic factors. That can be very helpful. In terms of the biomarkers, what do they do for us? Certainly, they can help us direct the right therapy. They can help us monitor the patient. They can help us predict the severity of the disease. I do think that we should follow this along because it’s going to be really helpful for us to discover more biomarkers that may be predictive for our patients.

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Experts outline biomarkers to measure asthma, highlighting eosinophil count and fractional exhaled nitric oxide levels.

Role of Biomarkers in Asthma

Let’s switch gears to barriers in the use of biologics in clinical practice. Dr White, do you see any trends or utilization differences, with the penetration of therapeutics, into the lives of patients with severe asthma, moderate to severe asthma, eosinophilic asthma, and difficult-to-treat asthma, among primary care providers or physicians vs the specialists?

In terms of thinking about how you titled this section, the barriers, I haven’t seen much of a trend of use in primary care physicians for biologics. There are multiple reasons for that. There’s a lot of what we’ve outlined, how complex it can be to decide what agent you might start a patient on. There’s going to be a barrier there. There’s definitely going to be a barrier in the ability to get insurance approval because these require some specialization in terms of the office staff and nursing staff shepherding it through the approval process. A lot of primary care practices may not have that infrastructure built in. I haven’t seen a big uptake in my area with primary care physicians using respiratory biologics.

But what I have seen is a lot more willingness to use these biologics at the point where it’s determined that they’re necessary. Because previously, 5 or 6 years ago, there was this sense that you’d start 1 or 2 of your worst patients on this and see how things would go for them, if these made a big change. In the allergy and immunology space, I definitely think we’ve seen a lot of comfort, recognizing that once a patient is poorly controlled, we need to think about these biologics. We have a lot of comfort using them now. They’re very safe. They’re very effective.

The other group I’ve seen a lot of uptick in is with our pulmonary colleagues, who also see a lot of asthma. Before these newer biologic agents, they may not have been using omalizumab in their practices for a variety of reasons, but now they’re much more willing and comfortable using these. It’s the same idea, reserving it for not just the very worst of the worst or the steroid-dependent asthmatics but also starting to more routinely consider this. At my institution, Scripps Health, it’s been great. We have a lot of sharing patients. Patients may have some confusion about what might be the best biologic, so they consult with us and still have a lot of their care directed by pulmonary. Those are the trends. I’ll bet it’s different in different parts of the country. Dr Chase and Dr Siri, I’m curious if you’ve noticed anything or any trends in your own practices.

 Overall we’ve seen similar trends with primary care providers. There’s a better awareness among primary care providers, who know that patients are coming and asking about these medications. Some have been talking with family members or friends who may have exposure to them. Others have been seeing television commercials of individuals breathing better, and wondering how they can be in that same category. The uptake has been higher with pulmonary colleagues over time. I hope they’ve learned that everyone in allergy is very friendly. A call to inquire about whether this patient is a good candidate for a biologic is much more common than ever before.

 There’s increased recognition from allergists that we’re allergy, asthma, and immunology experts. We’ve seen a lot of good collaboration with our pulmonary colleagues as well as our primary care doctors. Primary care has so many challenges, such as limited time. It’s helpful that there has been an increased movement toward biologics. There’s more understanding and education into what’s considered uncontrolled, what we accept as a number of exacerbation rates and corticosteroid systemic burdens over time. It’s been really helpful.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI:

 A couple of weeks ago, I had a patient come in on a follow-up with his wife and son. I thought, “They must be on their way to go shopping or to a restaurant.” It was the son who said, “Thank you for giving me my father back, because now I can play sports with him. He can breathe.” My patient was nodding; he’s a man of a few words. Those scenarios validate why we’re doing this and pushing the science to get better outcomes. Better outcomes, but not at the risk of worse adverse effects.

Dr Chase, earlier you described that give and take, the benefits and risks with the corticosteroids. With that in mind, what can be done to increase the availability of biologics in scenarios where patients need them and suffer from the deleterious effect?

That’s a great question. This is on all of us to educate our patients right off the bat. I love to tell patients, “Don’t worry.” I always have a couple of backup plans if we think they’re going toward the point of needing more assertive therapies in terms of biologics. That education is great. With settings like this, we all get to talk together, engage one another, learn from one another, and think more about how we can better educate our colleagues on the fact that these biologics exist. They’re there for us to use, and we wield them all the time. Let us be helpful to you if we can.

Access has always been an issue. For many individuals, access can be getting to a provider in an area that’s within a reasonable distance. We’ve seen some uptake with telemedicine with the pandemic, and that’s been lovely. But for an issue like asthma, we sometimes need to see patients in the office. However, all these biologics now, with the exception of reslizumab, can be self-administered. That’s huge. That’s what patients want: to take medication in the comfort of their own home, on their own time, knowing that there aren’t safety concerns about it.

With this group here, we’ve gotten very quickly comfortable with biologics being another step in the armamentarium we use to treat patients. We look at someone as they walk in the door and think, “I’ll bet they’re going to need a biologic at some point.” We’ve all done that. Now we have lots of years of safety and efficacy data. Hearing stories from patients validate that this was the right decision to make the right approach.

Finally, there’s the overall thinking about being part of the conversation. We need to let others know that this isn’t a field that’s stagnant. We’re getting new breakthroughs all the time. We need to encourage research further on asthma as a main issue for individuals in the United States and worldwide. There are even more to come. There are barriers, but there are lots of reasons to be excited about the future of asthma.

Experts discuss the use of biologic treatment in asthma by primary care physicians vs pulmonology specialists as well as overcoming barriers to biologic use through patient and physician education.

Trends in Biologic Treatment of Asthma

Dr Chase, you’ve initiated therapy, and the patient is on this course for weeks, months, or years. Are there situations where you decide you need to switch biologics? If so, how do you determine that? How do you come to the conclusion of which therapeutic to change to?

 That’s a tough question. When I think about starting someone on a biologic, I try my best to set very clear treatment expectations so that the patient knows what they’re hoping to get out of this new treatment, and I know what I’m hoping that they’ll get out of this treatment. For many patients, the easiest ways to think about that would be to decrease exacerbations; improve ability to breathe better, in terms of FEV1 [forced expiratory volume in 1 second]; a reduction in systemic steroid use; and if they have activities of daily living that they may not have been able to do.

At any point, if a patient is on a biologic, I’ll often tell them, “I’m going to ask your insurance to cover this for a year, and then I’m going to ask you to give me anywhere between 3 to 6 months.” I try to decide on those numbers, not arbitrarily but by looking at the clinical trials to see when the initial end points were studied. For example, there are very good data with most of these respiratory biologics, except maybe omalizumab, that you’ll see improvement within the first, second, or third dose. I’ll often ask patients to agree to stay on the medication for at least 3 months and then reevaluate, in terms of not only how they’re feeling about their asthma and their symptoms but also how the treatment is going—injections and whatnot.

At any point, if a patient is on a biologic and it seems they’re starting to regress, I like to reevaluate. I ask “Are you taking the medication as prescribed? Has there been any confusion about it? Are you able to access the medication? What else is going on?” I almost revisit my initial diagnosis, asking, “Did you get a new pet in the house? Is there something else that doesn’t explain this? Have you started to smoke again?” Maybe the person had previously not been smoking. We revisit the whole endotype and phenotype of the patient, reassess, get biomarkers again, and then go through the same decision process. I like to treat to almost complete control.

If a patient could be on a biologic for their asthma with a short-acting bronchodilator before exertion, or let’s say they have something on hand that they could use for a severe illness, we’re all looking forward to seeing data about patients hopefully able to come off other medications. For now, patients stay on their inhaled therapies, but that should be our goal—knocking it out of the park in some sense. Picking the newest 1 is the same thing we’ve all been talking about. It’s about shared decision-making, the endotype, and the phenotype and then trying our best to see if we can match that up with a therapy that seems acceptable to the patient.

Dr Siri, are there scenarios or situations where you might combine the biologic with a corticosteroid or other therapeutics for that matter?

 I’m going to remind you that these studies were done with standard-of-care therapy. If we’re talking about inhaled corticosteroids, those are always part of the baseline. Could we get to a different stage of the game at some point? As it stands, those are required because these are add-on treatments to the standard of care, which are inhaled corticosteroids.

As far as things like systemic steroids, in this era of corticosteroid stewardship, we’re trying to reduce the patient’s exposure to corticosteroids because we know how harmful multiple courses are. Even 2 exacerbations in a year can be to the entire body. In that respect, it was well illustrated, particularly by VOYAGE and VENTURE, which showed adolescents and children having corticosteroid-dependent asthma concurrently taking dupilumab and still having equal safety features. The most important is injection site reactions. There may be an increase in respiratory infections. But it’s largely well tolerated even when they were on systemic corticosteroids and reduce their level of systemic corticosteroids while having a reduction in asthma exacerbation rate. It’s not unreasonable to think a patient may be on both with the goal of reducing systemic corticosteroids and getting off them if possible. This was demonstrated in some of the clinical trials as with no increase in adverse outcomes when you have to use that. We have to take those particular patient factors into account.

Experts comment on switching from 1 biologic treatment to another, as well as combining biologics with steroids or other treatments in asthma.

Switching Biologic Treatment in Asthma

 Dr White, I’m going to give you a difficult question. How do you choose a biologic for a patient with severe asthma?

 That’s tough. It’s challenging. I’ll bet if you asked the others on the panel, you’d get slightly different answers. The beauty is that we have some great options. We’ve got some awesome tools. Our other specialties are probably a bit jealous of this crazy advancement that we’ve have. It’s a good problem to have. In terms of how we choose, the first step is thinking if the patient has evidence of type 2 inflammation. We’ve talked about that several ways. You can look at fractional exhaled nitric oxide, peripheral blood counts, and IgE level. All of those are biomarkers that help us predict patients who are going to have a good response. I start with that. Do they have type 2 inflammation? We have an option for treatment for patients who don’t have type 2 inflammation. That would be tezepelumab. One of the first branch points for me is thinking about tezepelumab in that situation.

Once we’ve looked at type 2 inflammation, I think a lot about the comorbidities. That’s come up a few times. Does the patient have nasal polyps? Do they have atopic dermatitis? Do they have allergic rhinitis? Those are all big factors because we have different expectations from the biologics or more evidence for their effectiveness. I’d definitely consider a patient who has comorbid nasal polyps, prioritizing 1 of the biologics that also has that indication. Think about a patient who has bad comorbid allergic rhinitis, who might consider putting on immunotherapy but you have a reason not to do it. That might be a good situation to consider omalizumab. Those are the main medical biomarker-driving factors that I think through.

The other part of the story is patient preference and their viewpoints on some of the options. These are all injectable medications with a slight variation of reslizumab, which is given intravenously. Patients are going to have thoughts about how often they want to self-administer. All these biologics we’ve talked about are given at different intervals: from every 2 weeks to every 4 weeks to even every 8 weeks. That can be a big factor that drives a patient’s preference. The final part of this is access. We need to pick something that the patient can afford and be able to use in the long term. These are intended for long-term use. That’s a big part of the decision, and we talk about this with the patient. That doesn’t happen during the first visit to the office, but we have to sort that out a little later. Those are the big factors that I put in. Every single time it’s a conversation the patient is part of. I don’t just order some lab tests and tell the patient that this is what I’ve decided to start them on.

Andrew White, MD, discusses choosing the right biologic for patients with severe asthma, considering factors such as asthma comorbidities as well as patient preference.

Andrew White, MD

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