Steroid-sparing Rx for Severe Asthma: What is In the Pipeline?

Asthma is a heterogeneous disease, characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and cough that vary over time as well as in intensity, accompanied by variable expiratory airflow limitation. For the majority of patients with asthma, inhaled glucocorticoids (IGCs) remain the gold-standard therapy because of their potent anti-inflammatory properties that reduce airway hyperresponsiveness and exacerbations, while improving lung function and quality of life. There remains a minority of patients, however, who respond poorly to IGCs or not at all.

The Global Initiative for Asthma guideline on asthma management was updated in 2015 (GINA 2015) and has incorporated the humanized IgG1k monoclonal antibody omalizumab as the fifth step in the treatment algorithm for severe refractory asthma. Omalizumab was approved in 2014 for the treatment of severe refractory allergic asthma and is a specific anti-IgE antibody.

At the ACCP 2015 meeting (CHEST 2015) in Montreal, Professor Paul O’ Byrne, chair of medicine in the faculty of health sciences at McMaster University, talked about the challenges of new drug development for difficult to control asthma. It is a complicated process given a heterogenous asthma population (severe eosinophilic asthma versus noneosinophilic asthma) with many and variable comorbidities (eg, rhinosinusitis, allergic bronchopulomonary asthma, obesity, gastroesophageal reflux disease, heart failure, COPD) that may or may not be complicated by cigarette smoking. Severe refractory asthma represents approximately 5% to 8% of all persons with asthma.  

The main goals for developing and approving new asthma controller medications are a documented reduction in the number of exacerbations as well as a reduction in the use of oral corticosteroids.

Dr O’Byrne highlighted the current candidates:

Mepolizumab^1,2 is a humanized monoclonal antibody that recognizesinterleukin-5 (IL-5) and has data from randomized controlled trials verifying significant reductions in asthma exacerbations. The agent was associated with improvements in other markers of asthma control. However, it has not been approved by the FDA yet.                

Benralizumab,³ an anti-IL-5 receptor α-monoclonal antibody which seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma with baseline blood eosinophils at  approximately 300 cells/μL, possibly due to targeting of the IL-5 receptor. Further investigation of benralizumab in phase 3 studies is warranted. This agent is also not FDA approved.

Reslizumab,⁴ another humanized anti-IL-5 monoclonal antibody, has results that support its use in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. FDA approval is expected in March 2016.

Dupilumab,⁵ a fully human monoclonal antibody that blocks IL-4 and IL-13, has shown efficacy in patients with asthma and elevated eosinophil levels. Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. However, it is not yet FDA approved.

Professor O’ Byrne suggested altering the strategy for new agent development by studying different agents in patients with milder disease profiles.

Primary care physicians have a limited armamentarium at present to treat asthma. As a result, we have to rely on corticosteroids and then deal with their side effects. That may change over the next year or so.

O’Byrne P. Airways Disorders NetWork Featured Lecture: New Biologic Pharmacotherapy in Asthma. Presented at 2015 American College of Chest Physicians annual meeting (CHEST 2015); October 26, 2015; Montreal, Canada.

References:

1. Ortega HG, Liu MC, Pavord ID, et al; the MENSA investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207.

2. Pavord ID1, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651–659. 

3. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879-890.  doi: 10.1016/S2213-2600(14)70201-2.

4. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Resp Med. 2015;3:355–366. 

5. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with foderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130-139.