The world of allergy biologics has exploded in the last year. New biologic agents are being developed that target specific and critical pathways to help manage patients who have asthma, hives, eczema and nasal polyps. Here I will focus on allergy biologics already approved for management of asthma and allergies as well as allergy biologics currently in development.
Researchers have relied on the development of biologic agents that target specific and critical pathways important in the pathogenesis of allergic and respiratory disorders to address the lack of responsiveness to conventional medications. A “one size fits all” approach does not benefit all patients and this is leading to “precision medicine” where each patient is identified and their biomarkers established and then a “tailored” approach is begun for their asthma or other allergy disease.
The first biologic approved by the FDA was omalizumab (Xolair) in 2003 for the treatment of chronic, persistent, moderate to severe perennial allergic asthma. Since then, omalizumab has approved for the treatment of chronic spontaneous/idopathic urticaria. Omalizumab’s mechanism of action is to block IgE and patients with asthma respond best to it when they have high allergen specific IgE, high exhaled Nitric Oxide and elevated blood eosinophils (greater than 300). The effects is that it decreases asthma exacerbations and it is approved for patients 6 years and older. There is a black box warning for anaphylaxis.
Another anti-IgE monoclonal antibody, ligelizumab, with approximately 50 fold greater affinity for IgE has been shown to reduce IgE more than omalizumab. However in the field of asthmatic patients, it did not have better effects than omalizumab and further development for asthma has been discontinued.
High eosinophil counts can persist in patients with severe asthma receiving multiple controller medications, including corticosteroids. Patients with persistent asthma and high blood eosinophil counts have more frequent exacerbations. IL-5 is an important cytokine in promoting and activating eosinophils. Blocking IL-5 should prove useful in asthmatic patients with eosinophilic inflammation. Three biologics use 2 different approaches in patients with severe asthma and eosinophilic inflammation.
Mepolizumab (Nucala) and reslizumab (Cinqair) are anti-IL-5 monoclonal antibodies approved by the FDA for the treatment of patients with severe persistent asthma with an eosinophilic phenotype. Benralizumab is being developed by AstraZeneca and it has been shown to help severe asthma patients cut back on oral steroids. Phase 3 trials were recently successful and their findings were recently published in the New England Journal of Medicine. Benralizumab has an FDA action date in the 4th quarter of 2017 and they plan to launch the product early 2018. Symbicort and Pulmicort are currently in AstraZeneca’s asthma portfolio and they are actively trying to get into the asthma biological sector with Benralizumab. Benralizumab binds to the alpha chain of the IL-5 receptor present on both eosinophils and basophils, resulting in depletion of these key inflammatory cells. AstraZeneca believes benralizumab is differentiated from Nucala and Cinqair as it binds directly to an IL-5 subunit. Whether this actually leads to better clinical results in asthmatic patients remains to be seen. Additionally, benralizumab is dosed every 8 weeks rather than monthly, which can give it a competitive advantage. More additional information on Nucala and Cinqair are below.
Quilizumab is an anti-M1 prime monoclonal antibody that depletes IgE expressing B cells to block IgE production. Quilizumab has been shown to block both early and late asthmatic responses and reduce serum IgE by approximately 40%. However, in a field trial for asthma, quilizumab did not show any therapeutic benefit and it is no longer being developed for asthma.
Lumiliximab is an anti-CD 23 monoclonal antibody that cross links CD-23 on B-cells, resulting in decreased IgE prodcution. However, lumiliximab failed in field trials for both patients with allergic asthma and those with rhinitis and is no longer in clinical development for either one.
Lebrikizumab showed improved FEV1 in asthmatic patients inadequately controlled with inhaled steroids. Its mechanism of action is an anti-IL-13 monoclonal antibody. The development of lebrikizumab for asthma has been stopped due to inconclusive results.
Dupilumab blocks both the effects of IL-4 and IL-13 by binding to the common alpha chain of the IL-4 receptor. Dupilumab has been recently approved for atopic dermatitis and it is being studied for asthma and nasal polyps. Dupilumab is dosed biweekly and administered at home, it resulted in reductions in asthma exacerbation and improvements in pulmonary function values regardless of pretreatment eosinophil levels.
Tralokinumab is an anti-IL-13 monoclonal antibody. It has had variable results in clinical trials, it is dosed biweekly subcutaneously. Markers for it are increased periostin levels and DDP-4 (dipeptidyl peptidase 4). It is still currently being investigated for asthma, it is in Phase 2 b trials.
AMG 157 is in clinical development for asthma. It is a monoclonal anti-TSLP (thymic stromal lymphopoietin) antibody. TSLP promote inflammation leading to eosinophilic inflammation. It is in phase 2 trials, its efficacy for asthma remains to be seen.
As with asthma, nasal polyps have been associated with increased IgE and eosinophils. Omalizumab has slightly decreased polyps, sinus blockage, nasal symptoms and improved loss of smell. Despite case reports, it is unclear whether there are definitive plans to gain approval of Xolair for this indication.
Nucala and Cinqair have been administered to patients with nasal polyps, neither have significantly improved nasal polyp scores. It remains to be seen if either if these medications will pursue an indication for nasal polyps.
Dupilumab showed significant improvements for nasal symptoms and reduction in nasal polyps. Although dupilumab showed promising results, further studies are needed to assess longer treatment duration, larger samples and direct comparison to other medications are needed.
Chronic spontaneous urticaria is associated with intense itching, hives and poor quality of life. A majority of patients do not respond to high dose second generation antihistamines.
Omalizumab markedly decreases circulating IgE levels and it has been shown to be an effective therapy for patients with or with circulating autoantibodies. The effects of Xolair are dose dependent, at the highest dose studied, 300 mg monthly, complete resolution was found in a significant amount of patients. Many patients are able to get the injection with a longer interval of time, in our practice we have seen the maximum of 12 weeks. Omalizumab is now added to urticaria therapy after failure of high dosages of antihistamines, H2-antihistamines, leukotriene antagonists and failure of high potency antihistamines such as doxepin and hydroxyzine.
Xolair has also been found to treat other forms of urticaria such as, cholinergic, cold, heat, aquagenic, delayed, pressure, solar and dermatographic urticaria.
Quilizumab did not cause clinically meaningful improvements in hives or itching, additional studies will be required to fully understand the etiology of this disease and the potential role of other IgE blocking strategies.
TNF alpha antagonists (etanercept, adalimumab and infliximab) have all been tried as options for various urticarial disorders. Promising results have been seen, but they have been in small case reports and anecdotally. In a retrospective study, 118 patients with chronic hives, 60% obtained complete resolution of hives with either adalimumab or etanercept. Interestingly, some of these patients have been unresponsive to omalizumab.
Rituximab is an anti-CD20 monoclonal antibody, some promising results have been demonstrated with chronic hives, however there are no clinical studies for it.
Intravenous immunoglobulin has shown to improve or lead to complete remission of chronic hives. A study has shown monthly infusions of low dose IVIG (0.15 g/kg) resulted in 90% of patients showing positive results.
As you can see, there are many allergy biologics available and still in development for a number of disorders including asthma, urticaria, atopic dermatitis and nasal polyps. In contrast to allergy immunotherapy (shots), the biologics discussed have not been shown to prevent the development of new sensitization and diseases such as asthma. Nonetheless, our abilities to treat allergic and immunologic diseases have improved considerably with the advent of the development of monoclonal antibodies and other allergy biologics.
If you do suffer from one of these diseases and conventional medications are not working, see your allergy doctor to discuss all treatment options.