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Supplements Therapeutic Advances in the Management of Type 2 Inflammatory Disease

Evolving Treatment Strategies in Type 2 Inflammatory Disease

In CALIMA, a randomized, double-blind, placebo-controlled phase 3 trial, investigators evaluated benralizumab as an add-on treatment in patients with severe, uncontrolled asthma and high eosinophil counts.38 The trial was conducted at 303 sites in 11 countries with patients aged 12 to 75 years; each had severe asthma, uncontrolled on medium-to-high ICS plus LABA, and a history of ≥2 exacerbations within the year prior to randomization. Of 2505 patients who were enrolled, 1306 were randomized; 425 were assigned to 30 mg benralizumab every 4 weeks, 441 to 30 mg benralizumab every 8 weeks, and 440 to placebo. The primary analysis population consisted of 728 patients. Annual exacerbation rate ratio for benralizumab versus placebo was the study’s primary end point. Patients administered benralizumab every 4 or 8 weeks experienced significantly lower exacerbation rates compared with those on placebo. Also, benralizumub was found to be a well-tolerated medication for patients with uncontrolled asthma with blood eosinophils ≥300 cells per μL.38

IL-4/13

Although the IL-5 pathway plays a significant role in asthma, the utility of the currently available IL-5 inhibitors is limited to a particular subset of patients with severe disease and high eosinophil counts. IL-13, another active pathway in the type 2 inflammatory process that contributes to multiple aspects of asthma, has also been the focus of therapeutic development in recent years.39 Lebrikizumab and tralokinumab, both IL-13 inhibitors, were evaluated for potential indications for asthma. Lebrikizumab met its primary end point in 1 of 2 phase 3 trials,40 and tralokinumab missed its phase 3 trial end points.41 Despite the challenges in targeting IL-13 in asthma, however, IL-13 was revealed to be a more promising pathway when targeted together with IL-4 via dupilumab.

In a phase 2 trial, the safety and efficacy of dupilumab was evaluated in patients with moderate to severe asthma with a blood eosinophil count of ≥300 cells/μL or sputum eosinophil level of ≥3% who had used medium-to-high doses of ICS plus LABAs. Patients were either administered 300 mg dupilumab (n = 52) or placebo (n = 52) once weekly. They were also given instructions to discontinue LABAs starting at week 4 and ICS from weeks 6 to 9. The primary end point was occurrence of asthma exacerbation. An 87% reduction in asthma exacerbation occurred with dupilimab (odds ratio, 0.08; 95% CI, 0.02-0.28; P <.001) and significant improvements were found in multiple measures of lung function and asthma control. Twenty-three patients (44%) with placebo and 3 patients (6%) with dupilumab experienced asthma exacerbation. AEs were more frequent in patients given dupilmab compared with placebo (eg injection-site reactions, nasopharyngitis, nausea, and headache).42

In 2018, the FDA approved dupilumab as an add-on maintenance treatment in patients aged ≥12 years with moderate to severe asthma and eosinophilic phenotype or corticosteroid-dependent asthma.7 The approval was based on results from 3 clinical trials showing that dupilumab reduced severe exacerbations and ICS use for improved lung function. It is the only FDA-approved biologic agent for patients with moderate to severe asthma.

In the first trial that led to FDA approval, patients were randomly assigned to receive subcutaneous dupilumab 200 mg, dupilumab 300 mg, or placebo every 2 or 4 weeks for 24 weeks. The trial had 2 subsets of patients: those with eosinophils >300 cells/μL and those with eosinophils <300 cells/μL. Increases in FEV1 were seen across all groups. Patients receiving dupilumab every 2 weeks experienced reductions in annualized rates of exacerbation of 71.2%-80.7% (patients with eosinophils >300 cells/μL) and 59.9%-67.6% (patients with eosinophils <300 cells/μL).43

In the second trial, lasting 52 weeks, participants received add-on subcutaneous dupilumab at doses of 200 mg or 300 mg, or placebo, every 2 weeks.44 Annual severe exacerbation rates and FEV1 change from baseline to week 12 were the primary end points. In the 200-mg group, there was a 47.7% lower rate of exacerbations with dupilumab compared with placebo (P <.001). The total rate of severe asthma exacerbations in patients who received 200 mg of dupilumab every 2 weeks was 0.46 (95% CI, 0.39-0.53); it was 0.87 in the placebo group (95% CI, 0.72-1.05). In patients with eosinophils >300 cells/μL, dupilumab reduced severe exacerbations 65.8% and 67.4% more than with placebo, in the lower- and higher-dose groups, respectively. In patients with eosinophil counts <300 cells/μL, dupilumab reduced severe exacerbations 35.6% and 44.3% more than with placebo, in the lower- and higher-dose groups, respectively. Across groups, dupilumab also improved FEV1 by 29% to 33%, compared with 14% to 16% for placebo.44 Post intervention, 52 patients who were administered dupilumab experienced blood eosinophilia, compared with 4 patients who were given placebo. Participants who were given dupilumab compared with placebo had overall better lung function and asthma control and considerably lower rates of severe asthma exacerbation.44

The third trial that led to dupilumab’s approval evaluated the effect of dupilumab in patients dependent on oral corticosteroids.45 Findings indicated that dupilumab reduced average daily oral corticosteroid use by 70%, compared with 42% for placebo. In the overall population, dupilumab resulted in a 59% reduction in severe exacerbations compared with the placebo group.45 Table 2 includes more information about ongoing trials evaluating dupilumab in asthma.46-49

Investigational IL Inhibitors for Asthma

Given the promise of therapeutic inhibition of IL pathways in asthma, research into inhibition of additional inflammatory pathways is underway. IL-17, for instance, has shown promise. Patients with severe asthma have been found to have IL-17A/F in their bronchoalveolar lavage fluid and airway tissue, correlating with disease severity and neutrophil inflammation.50 Several drugs have been tested to target this pathway, including brodalumab and secukinumab. Both of these agents have been approved for the treatment of psoriasis, but in these asthma investigations, both were found to either lead to severe mental health issues or did not demonstrate significant changes in Asthma Control Questionnaire Scores.50 Currently, CJM112, an anti–IL-17A agent, is being evaluated in a phase 2 clinical trial in patients with inadequately controlled moderate to severe asthma who have low IgE and blood eosinophil levels. Results are expected in July 2019.51

Predicting patient response to therapy remains a challenge for type 2 inflammation in asthma.52 Nevertheless, significant opportunity remains for the utilization of IL inhibitors as monotherapies and potentially in combination with other agents, to target type 2 inflammatory pathways and offer relief to patients with asthma.

Chronic Rhinosinusitis With Nasal Polyps

Traditional treatment options for CRSwNP include topical corticosteroids, nasal saline, short-term antibiotics (if infection is present), oral corticosteroids (for acute exacerbations), and surgery (after all other options have been attempted).53,54 Currently, no monoclonal antibodies are FDA approved for the treatment of CRSwNP, but several have been evaluated. For example, trial results have shown potential benefit for omalizumab in patients with CRSwNP and comorbid asthma.55 Additionally, drugs with a higher affinity for and increased ability to suppress free IgE are currently being developed.56

Treating Type 2 Inflammation With Interleukin Agents

Among other monoclonal antibodies, IL inhibitors have shown efficacy in the treatment of CRSwNP.54 In March 2019, dupilumab was granted Priority Review by the FDA for a Supplemental Biologics Application as add-on maintenance treatment for adults with severe, inadequately controlled CRSwNP. Data from the phase 3 SINUS-24 and SINUS-52 trials were presented at the 2019 American Academy of Allergy, Asthma & Immunology annual meeting in San Francisco.57 Results showed 42% and 27% improvement in sinus opacification at 24 weeks among dupilumab-treated patients with CRSwNP in SINUS-24 and SINUS-52, respectively, versus 4% and 0% with placebo. Treatment with dupilumab was also associated with 146% and 108% improvement in the ability to identify different smells at 24 weeks in SINUS-24 and SINUS-52, respectively, versus 19% and 7% with placebo. With dupilumab, improvements in HRQoL of 60% and 51% in SINUS-24 and SINUS-52, respectively, were also observed, along with improvements in lung function. Moreover, both trials showed reductions of 73% and 76% in rescue treatment with systemic corticosteroids and in nasal polyp surgery, in SINUS-24 and SINUS-52, respectively. The reduction in the use of corticosteroids extended to patients with comorbid asthma, as well (58.3% and 59.6% in SINUS-24 and SINUS-52, respectively).

IL-5 inhibitors are also under consideration for the treatment of CRSwNP. For instance, mepolizumab is a targeted anti–IL-5 monoclonal antibody that is currently in phase 3 trials. In the SYNAPSE study, participants are receiving mepolizumab or placebo every 4 weeks for 52 weeks. The patients are receiving standard-of-care treatments consisting of mometasone nasal spray, saline nasal douching, and occasional short courses of antibiotics and/or systemic corticosteroids. The study is ongoing and no results have yet been published.58

The IL-5 inhibitor reslizumab is also under consideration for treatment of CRSwNP. Post hoc results from phase 3 trials found that add-on reslizumab treatment reduced frequency of asthma exacerbations by 83% versus placebo.59

Future Directions

Significant advances regarding the inhibition of IL-4/13 within the past year alone suggest the broader importance of type 2 inflammation across atopic conditions. In asthma, following the FDA approval of dupilumab as an add-on maintenance treatment in patients aged ≥12 years with moderate to severe asthma and eosinophilic phenotype or corticosteroid-dependent asthma, the Global Initiative for Asthma recognized the role of type 2 inflammation in its April 2019 Pocket Guide for difficult-to-treat and severe asthma. The guidelines provide a blueprint for care that incorporates various IL-based therapies if type 2 inflammation is present.60 The guidelines also note several factors that should be considered when selecting an appropriate therapy, including local payer eligibility criteria, predictors of response, cost, dosing frequency, deliver route, and patient preference.

 
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