Activity Transcript

William W. Busse, MD: Hello, I'm Dr William Busse, professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine, at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. Welcome to this program, Foundations of Asthma: When to Consider Biologic Therapy. Please also look at other activities in this series, Foundations of Asthma -- Exploring the Allergic Component of Management and Exploring the Role of Biomarkers in Managing Therapy. I am joined today by Dr Thomas Casale, professor of internal medicine in the Division of Allergy and Immunology at the Morsani College of Medicine at the University of South Florida in Tampa. Dr Casale is also chief medical advisor for the Food Allergy Research & Education (FARE) program. Welcome, Tom.

Thomas B. Casale, MD: Thanks, Bill. A pleasure to be here today.

Dr Busse: Before we start, let's quickly summarize what we've covered in the prior activities. We've noted that asthma is a heterogeneous disease with multiple phenotypes and endotypes. We've also discussed that severe asthma comprises about 5% to 10% of total asthma cases but really accounts for the bulk of severity of disease in relationship to morbidity, mortality, and cost. Biomarkers are available to help us determine the risk for exacerbations and complications, and also possibly predict and monitor response to therapy. Biologic therapies are available as add-on therapy for patients with severe asthma that is poorly controlled or uncontrolled with conventional forms of therapy. Omalizumab, Tom, was the first biologic to be FDA-approved for the treatment of asthma in the United States, and it has been used in clinical practice for more than 15 years. How does omalizumab work?

Dr Casale: Well, Bill, I think we're learning a lot more about omalizumab and its mechanisms of action. But its primary mechanism is to bind to immunoglobulin E (IgE) at the same site that IgE binds to the high-affinity IgE receptor (FcεRI), which is on critical effector cells such as mast cells, basophils, and, in some cases, eosinophils. So essentially omalizumab prevents the IgE from binding to those cells and thereby prevents their activation by allergens. In addition, when you decrease IgE, which omalizumab does, you also decrease the expression of the high-affinity IgE receptor, and that too makes these cells less responsive.

Bill, we now have 3 interleukin (IL)-5 inhibitors that are FDA-approved to treat severe eosinophilic asthma: mepolizumab, reslizumab, and benralizumab. We also have an IL-4/IL-13 inhibitor, dupilumab, that received an indication in 2018 for severe eosinophilic asthma. Can you walk us through the mechanisms of action of these agents?

Dr Busse: Thanks, Tom. As you noted with the understanding of how omalizumab works, we're also getting a better understanding of how eosinophils and other type 2 cell endotype (T2) allergic inflammatory responses contribute to asthma. IL-5 is very important for regulating eosinophil maturity, growth, and also recruitment to the sites of inflammation. IL-5 causes these cells to undergo a terminal differentiation. Its effect is generated through IL-5 combining with the IL-5 receptor on the cell surfaces of eosinophils, basophils, and mast cells. Mepolizumab and reslizumab combine with IL-5 and therefore prevent IL-5 from interacting with eosinophils. Benralizumab, in contrast, is directed towards the IL-5 receptor alpha (IL-5Rα). When benralizumab binds to the receptor, it activates a process by which these cells undergo apoptosis and then are eliminated. Centrally directed towards IL-5, but with different mechanisms of action, decreasing the presence of the eosinophils.

The IL-4 and IL-13 cytokines play a very important role in regulating allergic inflammation. Dupilumab is directed against the IL-4 receptor alpha (IL-4Rα) and also blocks IL-13. IL-4 and IL-13 are generated by T helper 2 (Th2) lymphocytes, which cause these cells to undergo isotype switching and lead to the production of IgE, which then can become attached to mast cells. IL-4 acts upon the non-committed T helper cell, making it into a Th2 cell, which then generates IL-5, which then acts back on eosinophils. So when you block the IL-4/IL-13 receptor, you're having effects on IgE production and also on eosinophils, and through these mechanisms allergic inflammation is mediated.

Tom, how do we differentiate between the different biologics? Could you highlight a few of these distinguishing characteristics? Maybe you could start with omalizumab and then go on to the IL-5 receptor antagonists.

Dr Casale: Sure, Bill. These are important questions as you consider which of these to pick for an individual patient. As I indicated before, omalizumab is an anti-IgE monoclonal antibody (mAb). It's indicated currently for moderate-to-severe asthma in patients 6 years of age and older inadequately controlled with inhaled corticosteroids. I'd note here that the difference between omalizumab and the other biologics is the fact that it is the only one in the United States approved for 6- to 11-year-olds for the treatment of asthma. It's administered subcutaneously (SC) in the office setting at 75 mg to 375 mg every 2 or 4 weeks. The dose is determined by the total IgE, as well as the body weight (kg) of the patient. So it has some restrictions in that the IgE, at least for adults; the patient has to be within that 30 IU/mL to 700 IU/mL range in order to fit on the dosing paradigm. And the patient has to be in the dosing paradigm also for body weight.

Now IL-5 inhibitors, as you elegantly went through the mechanisms of action, have different indications. They are all added as maintenance treatment for severe asthma with eosinophilic phenotype in patients. But differences between the 3 are: number 1, reslizumab is only approved for patients 18 years of age and older, whereas mepolizumab and benralizumab are approved for patients 12 years of age and above. The second is that mepolizumab is dosed SC every 4 weeks, and benralizumab also dosed SC every 4 weeks for the first 3 doses, but thereafter can be dosed every 8 weeks. This is clearly different than reslizumab which has weight-based dosing -- 3mg/kg -- but is only approved for intravenous (IV) administration. The other biologic that's approved that you talked about is dupilumab, the humanized anti-IL-4 receptor antagonist, which is approved for patients 12 years of age and above as add-on maintenance treatment for moderate-to-severe eosinophilic asthma. This is different than the other biologics in that it is the only one approved for home administration. And depending upon whether the patient has oral corticosteroid-dependent asthma or not, the dose is going to be 300 mg for those with more severe disease on steroids versus 200 mg every 2 weeks self-administered at home if the patient so wishes. Tezepelumab and fevipiprant are both in phase 3 clinical trials currently.

All of these agents have a fairly good safety profile. There is a black box warning for the risk of anaphylaxis for omalizumab, which, in most studies, has been in the range of 0.1% to 0.2% of patients, and especially noted in the first 3 doses. Reslizumab has been reported to cause anaphylaxis in approximately 0.3% of patients. We do have some precautions for hypersensitivity reactions for the other agents as well -- dupilumab, benralizumab, and mepolizumab. Then finally, herpes zoster has been reported with mepolizumab. So a recommendation is that patients be given the zoster vaccine prior to the initiation of mepolizumab if the patient is 50 years of age or older.

Dr Busse: Tom, can you review some of the outcome measures that were used in clinical trials, and talk about why these outcomes may be relevant when physicians are deciding whether a patient should get a biologic?

Dr Casale: Sure, Bill. I think the important thing to look at is, with all of these agents, the primary endpoint in the clinical trials was a reduction in frequency of exacerbations vs placebo. That, as you pointed out, is very important because exacerbations are what really drive the healthcare costs for asthma patients. If you look at the reduction in frequency of exacerbations, they are all around 50%. Omalizumab perhaps a little bit lower, and dupilumab perhaps a little bit higher.

There are differences in the biologics in regard to whether or not they are able to improve lung function. Omalizumab has minimal effects on lung function. Reslizumab has been shown to improve forced expiratory volume in one second (FEV₁), especially in patients with elevated blood eosinophil levels -- that is, greater than 3% or 400 cells/μL. Mepolizumab, benralizumab, and dupilumab have all shown improvements in FEV₁ values. Dupilumab, of note, has shown improvements in FEV₁ within 2 weeks. That's a good marker perhaps of whether or not the drug will work in an individual patient.

The other difference is corticosteroid weaning or tapering. Omalizumab has some retrospective data on this, but no prospective data. Nonetheless, it has been shown to be capable of reducing inhaled corticosteroid doses. Mepolizumab, benralizumab, and dupilumab all have shown the ability to decrease total oral corticosteroid use, and facilitate discontinuation. This has not been studied with reslizumab.

Dr Busse: Tom, as an asthma specialist, how do you decide whether a patient needs a biologic therapy, and what are some of the considerations that other physicians and caregivers should be thinking about? Then once a decision is made to use a biologic, how does one choose an agent?

Dr Casale: Again, Bill, these are critical questions to the management of patients with uncontrolled asthma. I think the first thing that we always talk about is to make sure that the patient is actually taking the medications they were prescribed, and they are taking them correctly. We all know that with the multiple different types of inhalers that we have for these medications -- like inhaled corticosteroids and long-acting bronchodilators -- there is a learning curve and patients need to be instructed appropriately on how and when to take them. In addition, if a patient has significant allergies to an avoidable allergen -- for example, if you have a patient who's allergic to cats and they sleep with cats -- they may have chronic, worse asthma and it would be important to instruct them about allergen avoidance. Then shared decision-making. As we mentioned before, these biologics have different profiles in regard to how and when they're administered, and that's an important consideration for some patients. Some may not be able to come into the clinic every 4 weeks, so a drug like dupilumab may make more sense since they can administer it at home.

The other thing we have to consider in the management of patients using/being considered for biologics, is picking the right patient. If we assume that we've already made sure that the patient is adherent (using their inhalers correctly), comorbidities are appropriately treated, then those patients that require multiple doses of oral corticosteroids in a year (despite being on our best therapy) would be the most eligible patients to get a benefit from biologics. That would also include those patients that require low-dose oral corticosteroid to maintain control.

Now, the next part of your question was: which do I pick? Well, we don't have head-to-head studies for these agents, but we do have some general guidelines that one could follow. If you have a patient that has a significant allergic component and elevated blood eosinophils, they are very likely to respond to omalizumab. That should be considered the first choice for these patients.

And for patients that have non-allergic asthma but have a high blood eosinophil count, now all of these agents are approved for the eosinophilic phenotype according to the FDA, but they didn't define what that is. In general, anybody with 300 cells/μL or greater blood eosinophils are probably an eosinophilic type of patient. 150 cells/μL to 300 cells/μL is a bit more questionable. Less than 150 cells/μL, I think everybody would be comfortable saying, they don't have an eosinophilic phenotype.

Other considerations include the mechanism of action. Do you want to target IL-5 or the IL-5 receptor? How do you want to give the drug? We know that patients with severe asthma often have other comorbid conditions that are either associated with asthma, or associated with asthma and can also make asthma worse. So patients with nasal polyps and chronic rhinosinusitis (CRS), or patients with atopic dermatitis, which doesn't make asthma worse, but is associated with it. In this case, we're now seeing that some of these biologics are appropriate to treat not only asthma, but these comorbid conditions. Dupilumab, for example, is now approved for the treatment of CRS with nasal polyps. So if you have a patient with severe asthma and that condition, or a patient with severe asthma and atopic dermatitis, you might consider dupilumab, which has an indication for both. Patient weight -- some of these are weight-based dosing. In the case of omalizumab, if a patient is outside of the dosing range, that could be a real problem. Then patient preferences, as I described previously.

Dr Busse: Tom, another key question is: how long to continue a patient on a biologic? Do we have any guidance on this particular issue?

Dr Casale: Now Bill, that's another really good question that we don't have hard, vast data on. We do know that if a patient doesn't respond within 3 to 6 months of a given biologic, they are likely not to respond. So that's a good early cutoff for considering either stopping or switching to another biologic. As far as how long to treat, that's less clear. Patients treated with omalizumab for 3 years or 5 years, some of them have improvements in their overall asthma, but others have a worsening of their asthma once they are off omalizumab. This is also true for the IL-5 inhibitors. In the case of mepolizumab, it's been shown that if you discontinue it, eosinophils gradually increase over the 12 weeks.

Dr Busse: Biologics are becoming a very important treatment option for patients with severe disease. As you've indicated, using a biologic needs to consider the asthma phenotype, route of administration, the effect on comorbidities, and patients' preferences. One of the questions that needs to be addressed is: how to determine if efficacy is noted early in the course of treatment.

So Tom, thank you for joining me in this discussion. I also want to thank our audience for listening, and please proceed to answer the post-activity questions and complete the evaluation. Thank you.

This transcript has been edited for style and clarity.