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Clinical Updates on the Management of Asthma
Suzanne Bollmeier, PharmD, BCPS, AE-C
Advancements in Asthma Therapy and Their Impact on Managed Care

Clinical Updates on the Management of Asthma

Suzanne Bollmeier, PharmD, BCPS, AE-C
Bronchial thermoplasty (BT) distributes radio frequency energy into the airways via flexible bronchoscopy, which reduces airway smooth muscle mass and bronchoconstriction.54,55 Electrodes deliver thermal energy to the airway wall. When the energy comes in contact with tissue, it is converted to heat,55 which disrupts the actin-myosin interaction in airway smooth muscle, rendering it inactive.56 In a sham-controlled trial (placebo surgery-controlled), BT decreased ED visits, the frequency of severe exacerbations requiring corticosteroids, time lost from work/school after receiving BT and improved quality-of-life scores.57 BT was approved by the FDA in 2010 for patients older than 18 years who have severe persistent asthma not well controlled with an ICS and LABA.55 This treatment provided by interventional pulmonologists lends yet another option for patients not well controlled on a high-dose ICS plus LABA therapy.

Emerging Therapies Currently in Clinical Trials

Dissociated Corticosteroids

ICSs are the most effective anti-inflammatory therapy available and therefore are often the mainstay of treatment for patients with asthma.37 However, the use of ICSs is not devoid of AEs—that include immunosuppression, weight gain, and insomnia—especially with long-term administration. Therefore, efforts are being made to develop dissociated corticosteroids, which have reduced AEs yet retain their anti-inflammatory efficacy.37

ICSs bind and activate the glucocorticoid (GC) receptor. The activated receptor then binds in the promoter region of genes and activates transcription (transactivation) or interferes with activation of transcription (transrepression) on transcription factors.58 Transrepression is believed to be responsible for beneficial anti-inflammatory effects, while transactivation leads to the AEs of GCs.58 Selective GC receptor agonists (dissociated steroids) are compounds that would dissociate the transactivation function of GCs from the transrepression function, thereby having a larger impact on transactivation, and therefore, may have an improved therapeutic profile with fewer AEs.58 Many nonsteroidal GC receptor agonists are in development and undergoing clinical trials, but there are currently no approved therapies.

Biologics and Anti-Interleukin Agents

The understanding of inflammatory mediators and immunologic pathways implicated in asthma and the allergic response continues to increase. As such, a number of monoclonal antibodies targeting interleukins and IgE have been developed with the hopes of providing patients with tailored asthma treatment.18

Table 518-20,59-61 is a summary of biologics currently under investigation for use in asthma. Figure 117-20 is a simplified schematic of the inflammatory process highlighting where each anti-interleukin or anti-IgE agents works within the cascade.

Anti-IgE Biologics

Omalizumab was the first biologic therapy approved by the FDA for the treatment of severe asthma. Omalizumab is a humanized anti-IgE antibody that binds unbound IgE, which is central to initiation and propagation of the inflammatory response.59 It is currently the only FDA-approved anti-IgE therapy. The 2016 GINA guidelines now recommend the use of omalizumab or mepolizumab for patients in step 5 therapy (Table 11,19).19 Quilizumab and ligelizumab are newer therapies currently undergoing phase 2 clinical trials.59,61

In most cases, clinical trials that assess the use of novel monoclonal antibodies compare these agents to placebo. However, ligelizumab was recently compared with omalizumab in a head-to-head trial. Ligelizumab binds IgE with higher affinity than omalizumab, and the study results suggest it may be more efficacious than omalizumab with respect to both inhaled and skin allergen responses in patients with mild allergic asthma.59

Anti-Interleukin Biologics

In general, anti-interleukin monoclonal therapies act to decrease airway inflammation and prevent eosinophil activation.60 IL-5 stimulates eosinophil recruitment. Mepolizumab, reslizumab, and benralizumab are all biologic therapies that target IL-5. Mepolizumab and reslizumab are the only IL-5 antagonist biologics currently approved by the FDA for use in asthma. Benralizumab is slightly different in that it blocks the IL-5 receptor. Importantly, the 2016 GINA guidelines now recommend the use of omalizumab or mepolizumab for patients in step 5 therapy (Table 11,19).19

IL-4 stimulates the release of IgE, which ultimately binds and activates mast cells. Dupilumab, pitrakinra, and AMG-317 all target IL-4. Both dupilumab and AMG-317 block the IL-4 receptor. Pitrakinra is unique in that it is an inhaled therapy versus subcutaneous or intravenous. None of the IL-4 agents are currently approved by the FDA for use in asthma.60

Interleukin-9 (IL-9) binds to mast cells within the inflammatory cascade. MEDI-528 is currently the only anti IL-9 medication. It is not approved by the FDA for use in asthma, and it is currently in phase 2 clinical trials.60

IL-13 stimulates the release of IgE. Lebrikizumab and tralokinumab are the 2 agents that target IL-13. Neither are approved by the FDA for use in asthma, but they are currently undergoing phase 3 clinical trials.60

Interleukin-17 (IL-17) stimulates the production of Th17 cells, which are another class of T helper cells implicated in the propagation of the immune response. Secukinumab blocks IL-17, and brodalumab blocks the IL-17 receptor. Both of these agents are not currently approved by the FDA for use in asthma, but are undergoing phase 2 clinical trials.60

Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells Antagonists

Levels of prostaglandin D2 (PD2) are elevated in patients with asthma after an allergen challenge.60 PD2 released by mast cells, Th2 lymphocytes, and dendritic cells acts on the PD2 receptor, also known as the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). The CRTH2 receptor mediates the activation of T2 lymphocytes, eosinophils, and basophils in response to PD2. This suggests that CRTH2 antagonists may play a role in inhibiting the products of mast cell degranulation, leading to a decrease in the asthma allergic response.60 Figure 217-20 highlights where CRTH2 agents work within the inflammatory cascade.

Fevipiprant is an oral CRTH2 receptor antagonist recently assessed in a phase 3 clinical trial of 61 patients with moderate to severe asthma and an elevated sputum eosinophil count.62 Patients were randomly assigned to placebo or fevipiprant 225 mg orally twice daily for 12 weeks. The sputum eosinophil count significantly decreased in the fevipiprant group. There were no differences in reported symptoms between groups, and no deaths or serious AEs were reported.62

Other agents are currently under investigation and have shown some promise for use in patients with asthma.63,64 OC000459 is an oral CRTH2 receptor antagonist that demonstrated significant improvement in quality of life and nocturnal symptoms as compared with placebo in a phase 2a clinical trial65 and significant improvements in FEV1 as compared with placebo in patients with mild to moderate persistent asthma.63 AZD1981 is an oral CRTH2 receptor antagonist currently being investigated in phase 2 clinical trials. It has demonstrated a favorable safety profile, with potentially favorable results; however, more research is warranted to fully evaluate its use.64

Phosphodiesterase-4 Inhibitors

Phosphodiesterase-4 (PD-4) is the enzyme responsible for metabolizing cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP).66 GMP and cAMP regulate immune function.67 Inhibition of PD-4 leads to reductions in pro-inflammatory functions and immune cell activity.66,67

Roflumilast is an oral PD-4 inhibitor currently approved for use in COPD, and it is being assessed in phase 2/3 clinical trials for use in asthma. Roflumilast has been shown to be as efficacious as low-dose beclomethasone in improving FEV1 and asthma symptoms in patients with mild to moderate persistent asthma.68 Treatment with roflumilast significantly improved FEV1 lung function in patients with moderate to severe asthma in combination with montelukast.69 Roflumilast is considered safe; however, patients often experience gastrointestinal AEs, such as nausea, diarrhea, and weight loss.66

Conclusion

Asthma is a chronic condition of the airways defined by complex interactions of inflammation, airflow obstruction, and bronchial hyperresponsiveness.1 Despite many therapeutic options, the prevalence of asthma in the United States remains high and is expected to affect 100 million people by 2025.4 Additionally, not all patients with asthma respond to standard treatment options. As such, novel approaches to asthma management continue to emerge and are vital to the treatment of patients suffering from severe asthma.

Although many of the agents discussed appear promising and provide unique mechanisms of action to target various components of the inflammatory cascade, further work and clinical research is needed to elucidate the long-term efficacy and safety of these agents in patients with asthma. Fortunately, the GINA 2016 asthma guidelines now incorporate a few of the newer therapies and it is highly likely that more agents will be incorporated into the guidelines in the future. n

Author affiliation: St. Louis College of Pharmacy, St. Louis, MO.
Funding source: This activity is supported by an independent educational
grant from Novartis Pharmaceuticals Corporation.
Author disclosure: Dr Bollmeier reports receiving a grant from
GlaxoSmithKline.
Authorship information: Drafting of the manuscript, critical revision of
the manuscript for important intellectual content, and supervision.
Address correspondence to: sbollmeier@stlcop.edu.
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