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Supplements Therapeutic Advances in the Management of Type 2 Inflammatory Disease

Evolving Treatment Strategies in Type 2 Inflammatory Disease

Several IL inhibitors are in development for the treatment of AD. Lebrikizumab, which targets the IL-13 pathway, has shown promising results in a phase 2, randomized, placebo-controlled, double-blind study.14 Eligible adults with AD were required to use topical corticosteroids for 2 weeks and were then randomized 1:1:1:1 into 4 arms: a single 125-mg lebrikizumab dose; a single 250-mg lebrikizumab dose; 125-mg doses of lebrikizumab every 4 weeks for 12 weeks; or placebo every 4 weeks for 12 weeks. The primary end point was achievement of an EASI-50 score. Of the patients who received lebrikizumab, 82.4% achieved the primary end point with 125 mg doses every 4 weeks (P = .026). In the placebo arm, 62.3% of patients reached the primary end point. Patients who received a single dose of the drug experienced no significant improvement.14

In March 2019, lebrikizumab manufacturer Dermira revealed results of a 16-week phase 2b trial showing that 33.7% of patients treated with lebrikizumab every 4 weeks achieved clear or near-clear skin, compared with 15.3% of those receiving placebo. Additionally, 56.1% of patients in this group achieved a reduction of at least 75% from baseline in EASI score, while 36.1% of patients achieved a 90% reduction. Safety data were consistent with those of previous studies. The company is expected to initiate its phase 3 clinical trial program by the end of 2019.15

Tralokinumab is another agent in development that targets IL-13. In a phase 2b study, adults (N = 204) with moderate to severe AD were randomized 1:1:1:1 to receive 45 mg, 150 mg, or 300 mg of subcutaneous tralokinumab, or placebo, every 2 weeks for 12 weeks, along with topical glucocorticoids.16 The primary end point was the percentage of participants with a reduction of >2 grades from the baseline in the EASI score and with an IGA response (0/1 score) at week 12. At 12 weeks, patients receiving 300 mg of tralokinumab were significantly improved from baseline in EASI score versus placebo (adjusted mean difference, –4.94; 95% CI, –8.76 to –1.13; P = .01), and a greater percentage of participants achieved an IGA response (26.7% vs 11.8%). Those with increased IL-13 activity experienced greater responses.16 Phase 3 trials for tralokinumab are currently underway.

Several other agents are being evaluated that target IL pathways in AD, including IL-12, IL-23, IL-17A, IL-31/31R, TLSP, and anti-OX40. Additional areas of research, beyond IL pathways, may involve various immune and nonimmune mediated responses.17

Asthma

Asthma is typically characterized by airway inflammation, structural changes to the bronchial wall, and bronchial hyperresponsiveness with clinical episodes of wheeze, shortness of breath, chest tightness, and cough.18

Treatment Overview

Guidelines from the National Asthma Education and Prevention Program for initial diagnosis and treatment of asthma involve controlling the disease with appropriate medication for long-term management and making therapy adjustments as necessary on an individual basis. Initial visits consist of diagnosis, assessment of severity, initiating and demonstrating medication use, developing a treatment plan, and scheduling a follow-up visit. Follow-up appointments are recommended to assess how the patient is responding to treatment and to determine whether adjustments are needed to the asthma therapy plan and/or medication.19

The existing goal of asthma therapy is to provide long-term management and improve overall symptom control. To successfully achieve disease control, it is essential to do the following to reduce impairment and risk19:
  • Avoid exacerbations.
  • Prevent chronic symptoms.
  • Decrease use of short-acting β2 agonists.
  • Maintain lung function and normal activities.
  • Minimize the need for emergency department visits and hospitalizations.
  • Reduce AEs.
  • Prevent loss of lung function.
Additionally, patient education, environmental control, and management of comorbidities play an important role in asthma management.19

Several therapeutic options are available to help control disease symptoms and reduce exacerbations. Often, treatment selection is dependent on disease severity.20

Corticosteroids

Two types of corticosteroids are indicated for the treatment of asthma. Inhaled corticosteroids (ICS) provide the most effective long-term control for persistent asthma, because they reduce inflammation and prevent symptoms when administered daily (recommended use).19 ICS have shown activity on multiple inflammatory cell types, including mast cells, eosinophils, neutrophils, macrophages, and lymphocytes, as well as inflammatory mediators (eg, histamines, eicosanoids, leukotrienes, cytokines). The benefits of ICS are not immediate; it may take 1 to 2 weeks or longer for benefits to be completely present.21 Oral corticosteroids may be given as a short-course treatment if a patient is having an acute exacerbation or in cases of uncontrolled severe disease. Regardless of delivery mechanism, chronic use of systemic oral corticosteroids is associated with a significant occurrence of AEs.22

β2 Agonists and Leukotriene-Receptor Antagonists

Short-acting β2 agonists (SABAs) are used for quick relief of asthma symptoms to manage acute exacerbations. This medication class is indicated for the treatment of bronchospasms in patients with obstructive airway disease and exercise-induced bronchospasms.23 Long-acting β2 agonists (LABAs) may be added to the treatment plan for patients who are not well controlled on ICS or for those whose disease calls for both an ICS and a LABA. As SABAs do, LABAs exert their effects by agonizing β2 receptors, leading to the relaxation of bronchial smooth muscle.24 LABAs should not be used as monotherapy for long-term control.19

Leukotriene-receptor antagonists (LTRAs) are indicated for the treatment of chronic asthma and for prophylaxis. The most commonly used LTRAs for asthma treatment are montelukast and zafirlukast. Zafirlukast was the first LTRA to receive FDA approval to prevent exercise-induced bronchospasms in both adults and children with asthma.25-27

Monoclonal Antibodies

Not all cases of asthma can be appropriately treated with ICS, β2 agonists, and LTRAs. For patients with severe asthma, monoclonal antibodies can reduce airway inflammation and address underlying type 2 inflammation.28 One agent that targets this pathway is omalizumab, an anti-IgE antibody that has been shown to slow airway responses to inhaled allergens. Approved by the FDA in 2003, omalizumab has also been shown to reduce exacerbation rates and maintenance doses of oral corticosteroids.29

Targeting Type 2 Inflammation With Interleukin Inhibitors

For subgroups of patients who have severe asthma, in whom standard treatment options are not successful, treatment may be needed to target specific inflammation pathways.30 Targeting various IL pathways and receptors directly has been shown to offer important benefits.

IL-5

The first IL-based agents approved for the treatment of asthma were IL-5 inhibitors. As described in the previous article (p. 4), IL-5 is a crucial cytokine in multiple asthma phenotypes and places selective action on eosinophils, which in turn worsens asthma symptoms, inflammation, and overall severity of the disease. As add-on maintenance therapies, drugs that target IL-5 or IL-5Ra (the IL-5 subunit) have shown benefits in patients with refractory asthma with an eosinophilic phenotype who continue to have inadequate asthma control or exacerbations despite corticosteroid use. Three IL-5 inhibitors have been approved for asthma.31

Mepolizumab, approved by the FDA in 2015, is an IL-5 receptor antagonist indicated as an add-on maintenance treatment for patients aged ≥12 years with severe asthma and eosinophilic phenotype.32 MUSCA, a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3b trial evaluated mepolizumab and its effect on health-related quality of life (HRQoL) in patients aged ≥12 years with severe eosinophilic asthma, with a history of ≥2 exacerbations that required treatment within the year prior to the study.33 Enrolled patients received 100 mg mepolizumab (n = 274) or placebo (n = 277). The mepolizumab group had significant improvements, versus the placebo arm, from baseline to week 24 in St George’s Respiratory Questionnaire total scores (mean least squares change –156 [1.0] vs –7.9 [1.0]). More patients who received placebo reported 1 or more on-treatment AEs compared with those who received mepolizumab (74% vs 70%). Investigators also found that mepolizumab contributed to significant HRQoL improvements in patients with severe eosinophilic asthma.33

In 2016, the FDA approved the IL-5 inhibitor reslizumab as an add-on maintenance treatment for use in patients aged ≥18 years who have severe asthma with an eosinophil phenotype.34 Results from a phase 3 study testing reslizumab in patients with poorly controlled asthma and eosinophils demonstrated efficacy and good tolerability in patients with high eosinophils, and the agent was well tolerated.35 In patients who had baseline eosinophils <400 cells/μL, there was no significant improvement in forced expiratory volume in 1 second (FEV1) in either patient population. However, those with eosinophils ≥400 cells/μL who were treated with reslizumab, compared with placebo, experienced considerable improvements in FEV1, Asthma Control Questionnaire-7 responses, SABAs used, and forced vital capacity. The reslizumab cohort also experienced fewer AEs than the placebo group.35

Benralizumab, FDA approved in 2017, is indicated as an add-on maintenance treatment for patients aged ≥12 years with severe asthma and eosinophilic phenotype.36 In SIROCCO, a randomized, double-blind, parallel-group, placebo-controlled phase 3 study, researchers assessed the safety and efficacy of benralizumab at 374 sites in 17 countries.37 Of 2681 recruited patients aged 12 to 75 years, 1205 participants met the study criteria. Patients were randomized to receive either placebo, benralizumab 30 mg every 4 weeks, or benralizumab 30 mg every 8 weeks (n = 398). Results showed that when given every 4 or 8 weeks, benralizumab reduced the annual asthma exacerbation rate. At week 48, both benralizumab dosing regimens considerably improved prebronchodilator FEV1 compared with placebo. Common AEs were worsening asthma (observed in 13% and 19% of patients receiving benralizumab and placebo, respectively) and nasopharyngitis (observed in 12% of patients treated in the 2 benralizumab groups and the placebo group).37

 
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