Shifting the Treatment Paradigm of Severe Asthma With Novel Biologics - Episode 7
Nicola Hanania, MD, MS, and Geoffrey Chupp, MD, review the current FDA approved agents and IL-5 inhibitors for severe asthma, including omalizumab, mepolizumab, reslizumab, and benralizumab.
Reynold Panettieri Jr, MD: Nic, you’ve had some really amazing publications in this space with regard to the FDA-approved omalizumab [Xolair]. Can you spend just a moment on that? What’s the target? What are the factors for when you pull the trigger to use omalizumab?
Nicola Hanania, MD, MS: Omalizumab is 1 of the earliest biologics we’ve had: for more than 15 years. It’s approved for allergic asthma, so the patient has to have perennial allergies: mainly by skin testing or blood testing. If the patient doesn’t have allergic asthma, they’re not candidates for omalizumab. As you know, it’s given either every 2 weeks or every month, depending on the IgE level. So the IgE level is important. But weight is also important. There’s limitation to the dosing because in very obvious patients who have very high IgE, we’re limited in using omalizumab injections. The bottom line is this drug has been shown in allergic asthmatics. It doesn’t matter what their eosinophil and other T2 markers are, there are some signals suggesting that patients with high T2 signal may benefit better with omalizumab. It doesn’t have to be there for it to have an effect on using the exacerbation. The effect on lung function is modest at best, but it has a small effect on exacerbation. It’s the only medication that targets IgE among the other biologics we have. It’s also approved for children, so for very young children with allergic asthma, that’s a positive. More recently, the FDA has approved it for home administration. It does have a black-box warning for possible anaphylaxis, but it got approval for home administration.
Reynold Panettieri Jr, MD: That was exciting—that new indication, the new use at home—because we’ve had some 16 years of experience with omalizumab. Let’s transition in the high-T2 space. Geoff, why don’t you walk us through the 3 agents? There are anti-IL5s. We have 6 agents, 6 biologics in this space. Let’s specifically look at the IL-5s. Geoff, where do you start to say, “This is an anti–IL-5 patient?”
Geoffrey Chupp, MD: It’s fairly clear that eosinophils are very strongly linked to IL-5. This has to do with the fact that IL-5s, the canonical growth factor, is the primary growth factor for eosinophils, and drives their expansion in the bone marrow and migration in the blood and into the lungs. Individuals who have evidence of eosinophilic inflammation that’s refractory to standard therapies are the ones we really consider eosinophilic. The drugs, of course, target these are biologics as well, similar to omalizumab. But instead of binding the IgE and preventing the allergic reaction, they target the IL-5 pathway. Interestingly, the first 1 approved was reslizumab [Cinqair], and it was given IV [intravenously].
It’s dosed by weight, so it was very successful, but it has become a little less commonly used because of the IV dosing that’s required, especially during the pandemic. This drug binds directly to IL-5, which prevents it from interacting with the IL-5 receptor, so it has effects on reducing the eosinophil counts in the blood, improves asthma control, and reduces flares. The second 1 that came out was mepolizumab [Nucala], an anti-IL-5 drug that really was part of this new wave of biologics in clinical trial data that had a couple of effects. These trials really allowed us to zero in on the importance of exacerbations as an end point for patients, as opposed to peak expiratory flows that we studied in the last decade. But it also helped really lock in on the eosinophil count as a biomarker for these patients and led to us phenotyping individuals. Now, we can track the blood eosinophil count in patients in the clinic with asthma always getting a CBC [complete blood count] and differential.
This showed improvements in exacerbation rates, disease activity scores—both by ACT and St George’s Respiratory Questionnaire—and also improved lung function, FEV1 [forced expiratory volume in 1 second]. The most recent biologic was benralizumab [Fasenra]. This is an interesting drug because we start to see how it looks as if there are differences between targeting the soluble cytokine vs targeting the receptor of the cytokine. Benralizumab targets the IL-5 receptor, so we think of it more as directly antieosinophilic, because it has 2 effects: It blocks the interaction of IL-5 with its receptor, but it also brings in natural carrier cells, which drive antibody-directed cellular cytotoxicity. So there’s apoptosis of these eosinophils in the tissue. The trials for benralizumab showed strong effects on reducing the exacerbation rates, but probably overall there were better effects on lung function improvement compared with the other IL-5 biologics.
Reynold Panettieri Jr, MD: That was a great review of the anti–IL-5s. I agree completely. I want to highlight 1 aspect: The eosinophil, in this case, becomes a pharmacodynamic [PD] biomarker—a PD marker, so to speak. What does that mean? That means that when we give the drug, the target is obliterated, and we know the drug worked on the target. We didn’t answer the question whether it worked to improve the asthma, but we know the drug worked, and very few drugs—that we have— have PD markers, or pharmacodynamic biomarkers. For example, when we use a big agonist, I have no idea whether cyclic AMP levels go up in airway smooth muscle. So we’re now redefining a new approach in the use of biologics in which we can determine if the drug has affected the target. Then we, as the providers, determine whether the disease state is improved. This is a paradigm shift. It’s a unique aspect, so great job on the anti–IL-5s and the anti-IgEs.
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Transcript Edited for Clarity