Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: Dr Siri, when is it time to think that we need to start using biologics, new era biologics, on these patients with severe asthma or moderate to severe asthma?

Dareen D. Siri, MD, FAAAAI, FACAAI: I love what you said about stepping up the therapy and providing excellent care. These are good opportunities for us. As we’re progressing on the GINA [Global Initiative for Asthma] guidelines, which Dr White talked about so brilliantly, we get to the arrival point of the patients with severe asthma. That’s typically someone who has moderate asthma…and doesn’t have control on their current baseline therapy. So, the patients with severe asthma have already been put on the standard maintenance in ICS, an inhaled corticosteroid, with a LABA, a long-acting beta-agonist, and maybe additional controllers, whether they’re leukotriene modifiers or LABAs. And this applies to the patients with moderate asthma who continue to have a higher risk of exacerbation and frequent use of medication. So that’s the big target. The second is thinking about those patients, and it’s illustrated nicely in the GINA 2023 guidelines: thinking about the severity and also thinking about whether they’re at risk for exacerbations. The third part of that, looking at the last column in the GINA guidelines, is their phenotype/endotype. Do we think that they have inflammation that could be targeted with some of these medications, whether that is an IL-5 antagonist or IL-5 receptor antagonist or an IL-4, IL-13 antagonist, IL-4 receptor α antagonist plus IL-13? If they could have that type of inflammation, they could be a candidate for a biologic. In addition to that, we want to…make sure the diagnosis is correct, that the patient’s asthma is otherwise optimized with those therapies for comorbidities, that their allergens are controlled, that they’re doing their very best in terms of adherence, and those kinds of things before we reach that point. And those are well illustrated in other parts of the GINA guidelines as well.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: I will turn it back to you, Dr White. I’d like you to go through the mechanisms of action and the indications for the new biologics that we started to touch on that have been approved for severe asthma.

Andrew White, MD: It’s been an exciting time in our field watching these develop and seeing the huge changes in what we’re able to offer our patients. It’s been very interesting as we try to learn about what pathways these biologics are targeting. And what else does this teach us about type 2 immunity? I think I would put these into 4 broad classifications. The first mechanism of action is targeting IgE. IgE is an allergic antibody. We think about it as a way of transducing an allergic reaction to dust mites or peanuts, where it’s sitting on the surface of our mast cells. It gets cross-linked with exposure; the mast cell releases a lot of its mediators. So by binding to IgE, we’re able to modify that pathway. The medication that does that is omalizumab. So that’s the first mechanism of action. The second broad mechanism of action is targeting the eosinophil itself. We’ve talked about eosinophilic asthma already, and we think about type 2 immunity. So the eosinophil is one of the core cells we see associated with that. So targeting the eosinophil makes sense. We’ve got 2 broad ways to do that. The first is to target IL-5. IL-5 is a cytokine. It’s critical to lead the eosinophil to be active and live longer. So that cytokine is produced at various parts of our body to drive that process forward. By targeting eosinophils, we can target IL-5 itself. We have 2 monoclonal antibodies that do that. We have mepolizumab and reslizumab. And the other way to target the eosinophil is to directly target the cell itself. You can also target IL-5, but in this situation, it’s the receptor for IL-5. That IL-5 receptor predominantly lives on the eosinophil. So we have a monoclonal antibody that targets that receptor, and it actually leads to acceleration of apoptosis of eosinophils and eliminates them from the peripheral bloodstream almost immediately, and that is called benralizumab. The second broad mechanism of action is targeting eosinophils. The third would be targeting type 2 inflammation more broadly. So it’s not just eosinophils. It’s not just mast cells. There’s a combination of other factors involved in type 2 inflammation. So the next mechanism would be targeting IL-4 receptor α. And it turns out that particular receptor exists in 2 different cytokine receptors. So IL-4 receptor α is both in the IL-4 receptor and the IL-13 receptor. By blocking that receptor subunit, you’re able to affect signaling through both of those cytokines. Those are important in type 2 inflammation, and dupilumab is the monoclonal antibody that acts there. And then the final category would be a broader look at inflammatory pathways involved in asthma, and that’s TSLP, thymic stromal lymphopoietin, and that is called an alanine. It’s released in the context of asthma. We mostly think about this as coming from the airway, and it can broadly affect a lot of different pathways downstream, including type 2 pathways, but also some pathways that may not be related to type 2. So we do have a monoclonal antibody that binds to TSLP. By decreasing TSLP, you’re going to have a significant effect on that pathway, and that’s called tezepelumab. Those are the 4 categories. I did mention all 6 drugs. Correct me if I’m missing anything. Starting in chronological order, omalizumab was the first approved. That was approved in 2003 when it was approved for asthma. It also has been approved now at a younger age for pediatric asthma. The next is going to be mepolizumab, which was approved in 2015. So later we had a lot of experience with omalizumab. And 2015 is when we had several more developments. Mepolizumab is approved for both adult and pediatric asthma. Then reslizumab closely followed. Reslizumab is a bit different. Reslizumab is administered intravenously, and it’s dosed based on weight. It’s approved for adult patients with asthma and came out in 2016. Then benralizumab in 2017 was approved for asthma in patients 12 years or older. Then dupilumab came out in 2018, where it was initially approved for adults and patients 12 years or older with asthma, and the pediatric indication came on later. Finally, tezepelumab is the most recent and was approved in 2021 for patients 12 years or older with asthma. All these really looked at exacerbation frequency as one of the core primary end points, because this is one of the big features of our patients with severe asthma: They tend to have many exacerbations. So, the great benefit of this, in addition to a lot of other benefits in their studies, is really looking at decreasing these exacerbations, which…are driving systemic corticosteroids and having negative long-term effects on our patients’ health.

Transcript edited for clarity