Unlocking asthma the mAb wayJune 11, 2019
Asthma is a heterogeneous disease, characterised by inflammation of the air passages of the lungs.
World over, an estimated 235 million people suffer from asthma, a chronic condition characterised by symptoms such as difficulty in breathing, tightness in the chest and wheezing.
Caused by a combination of complex environmental and genetic interactions, the underlying mechanisms of this airway disorder is yet to be fully figured out.
Since there is no known cure for the disease, symptoms are controlled through therapeutic interventions. Corticosteroids, mostly in the inhaled form, is the centerpiece of the current treatment to check the inflammatory process. Inhaled bronchodilators and/or leukotriene pathway inhibiting agents are also added if symptoms remain uncontrolled.
The drug regimen, comprising inhaled corticosteroids (ICS) and long-acting beta agonists (LABA), has been used to manage asthma symptoms successfully in most of the patients.
However, 10%–20% of patients do not achieve control with the current gold standard of care. This population of severe refractory asthmatics is at increased risk of morbidity and mortality, and make up the majority of the economic costs of asthma, studies indicate.
Also, the long-term use of some asthma treatments, especially oral steroids, come with noticeable risks.
Search for newer, safer and better treatments for severe asthma has opened the door to exploring and identifying different types of this disease.
Over the last decade, specific phenotypes and endotypes of asthma have been evaluated, leading to more personalised, targeted approaches to fit patient-specific disease, abandoning the one-size-fits-all treatments.
A better understanding of the role of the inflammatory modulators involved in asthma paved the way for the development of therapies using biologics as a treatment option.
Today, biologic therapies, which are made from living organisms using recombinant DNA technology, are increasingly being considered in patients with severe asthma. People with a severe form of the disease constantly struggle with persistent symptoms. This makes it tough for them to maintain a good quality of life.
Traditionally, asthma is classified based on severity. Experts today hold that asthma is no longer single disease. Rather, it is increasingly recognised as an umbrella term — just like cancer or arthritis — for various phenotypes. Finding ways to identify subgroups that respond well to different types of treatments is a current, critical goal of asthma research.
One of these phenotypic pathways is thought to be type 2 pathway — T helper 2 (Th2). About half of the individuals with severe asthma exhibit the type 2 phenotype, with increase in Th2 cells. There is an increase in the number of CD4+ T cells, predominantly TH2 cells, in the airways of asthmatic patients, whereas in normal airways, TH1 cells predominate. TH2 cells have a central role in asthmatic inflammation. Also called the “atopic” pathway, it refers to a hypersensitive reaction to an allergen. Patients with typ2 phenotype release cytokines such as interleukin [IL]-4, IL-5, IL-13, which drive immunoglobulin E (IgE) production.
Targeting the cause
The majority of asthma patients are also allergic. IgE, the antibody intimately involved in allergic responses, is the target of omalizumab, the first approved monoclonal antibody treatment for asthma.
“Since omalizumab was first introduced to the United States market in 2003, it, and other more recent biologics for asthma, have made a tremendous difference in the lives of many asthmatics. Their impact can be likened to the introduction of the combination of inhaled steroids and long-acting beta agonists in the 1990s, which allowed a number of asthmatics to attain greater control of their asthma and a number of severe asthmatics to get off of systemic steroids,” says Dr Andy Nish, MD Fellow of American Academy of Allergy, Asthma & Immunology (FAAAAI), USA.
The asthma biologic drug research pipeline today contains 12% monoclonal and 17% non-monoclonal antibodies.
Some groups of white blood cells, such as eosinophils, are found to be critically involved in the inflammatory process in the airways that results in the loss of lung function in asthma. Several products have been developed to inhibit the production, the function, and the survival of eosinophils. These antibodies seem to work particularly well in individuals with high eosinophil counts prior to treatment and who have not responded to current treatment with inhaled corticosteroids. Collectively, these products are well tolerated and are effective in reducing eosinophil numbers and preventing asthma exacerbations.
Multiple antibodies seek to tackle cytokines, which are key in fuelling allergic-type responses and inflammation. But the therapeutic agents that single out individual cytokines for targeting proved to be largely ineffective due to the overlapping effects of cellular signalling proteins. However, antibodies blocking the effect of more than one cytokine have shown promise.
Mepolizumab, reslizumab, and benralizumab are targeted towards IL5, a cytokine that promotes both the activation and longevity of eosinophils. Dupilumab is an anti-IL4 cytokine antibody which is essential for Th2 cell polarization. Whereas, biologic tralokinumab, that targets IL13 cytokine, is currently under phase 2 development. IL13 is associated with periostin production in the bronchial epithelial cells, ultimately resulting in smooth muscle contraction, mucous production, airway remodelling and hyper-responsiveness.
Today, clinicians have more than 10 years of clinical experience with IgE targeting omalizumab and extensive trial data with anti-eosinophil antibody mepolizumab. Unlike for most drugs, outcomes in clinics with omalizumab have often been better than those seen in clinical trials. It is considered a surprising feature of omalizumab in clinical practice.
Rising incidence; dearth of biomarkers
Estimates show that the incidence of asthma may have increased as much as 12% over the past decade. Several theories postulate as to why the incidence of asthma is on the rise.
First, asthma is more recognized and coded as such, as opposed to in the past, when it may have been diagnosed using terms such as bronchitis, explains Dr Nish.
According to him, allergic diseases, in general, have been increasing; not only asthma, but also allergic rhinitis, food allergy and atopic dermatitis. “One theory is called the hygiene hypothesis, that our lymphocytes no longer have to fight infection as much as in the past, so they are becoming more Th2 cells and producing allergic disease,” he remarks.
Air pollution has been linked to increased incidence of asthma in children, as has exposure to cigarette smoke, particularly if the mother smokes while pregnant. In addition, if a child’s diet is leading to obesity, it can be associated with an increased risk of asthma. Caesarean births change gut flora and increase the risk of asthma too. So, the rise in asthma is likely multifactorial.
Even though biologic therapies allow the selection of patients suitable for intervention with antibody infusions, defining a set of predictive and monitoring biomarkers to assess the likelihood of a patient who will respond to a biologic continues to be a challenge. It is also difficult to determine whether there is a favourable response to continuing the biologic. Biomarkers, which will provide a profile of those patients most likely to respond favourably and also to discontinue medication if there is a low likelihood of a response, are yet to be a reality. It took several years to define the subgroup of patients with severe asthma who respond to anti-IL-5 treatment.
The concept of subtypes of asthma is new and clinically still evolving. Much has been made of endotypes, with many different pathways described as potentially contributing to the asthma phenotype. There has been much debate about type 2 (IgE and eosinophilia driven by IL-4, IL-5 and IL-13) and non-type 2 asthma. The RASP-UK study, adjusting therapy according to type 2 biomarkers, exhaled nitric oxide, blood eosinophils and serum periostin (an IL-13 induced epithelial protein), should help define which patients have controlled type 2 disease, and which have a non-type 2 mechanism driving their symptoms.
The outlook for severe non-allergic asthma, however, is less rosy at present. This is because a lot of efforts have been devoted to finding effective drugs for severe allergic asthma, but severe non-allergic asthma has not been the focus of as much research. This is an area where more research is urgently needed, believes leading organisations like Asthma UK.
But many researchers are still uncertain about the existence of non-type 2 asthma in the severe asthma population.
“For the Th17 (non T2) type asthmatic, there are currently no highly effective biologics,” points out Dr Nish.
Clinical trials should inform on the role of biomarkers in determining treatment response. Benefits of anti-IL-5 approaches with mepolizumab, reslizumab and benralizumab, and dupilumab (anti-IL4/IL-13) have been documented by large clinical trials. Phase III studies of lebrikizumab (anti-IL-13) did not show significant clinical benefit compared to placebo. The lebrikizumab phase 3 studies did not enrich for exacerbations.
Efficacy in children — Expanding evidence
Asthma in childhood is quite different from asthma in adulthood. Phenotypically, paediatric asthma is more commonly allergic in nature. Likewise, the prevalence of asthma is higher in male children, whereas adult females have more severe and persistent disease. Hence, results from adult studies may not be extrapolated to the paediatric population. Evidence is expanding for biologic therapies such as omalizumab in children, despite the fact that evidence is limited for most of these drugs in the case of adult-onset asthma.
Omalizumab is now approved up to 6 years of age in some countries. This makes it the first choice for children with severe asthma if the serum IgE is within limits. Mepolizumab and benralizumab, the anti-IL5 therapies, are available for use in some countries for adolescents of 12 years of age. The treatment is likely to reduce exacerbations in cases where the blood eosinophil count is more than 300 cells/µL and perhaps 150 cells/µL. Dupilimab, which has been found not having significant adverse effects in adult studies, is being considered for home administration.
Adjunctives for uncontrolled asthma
Omalizumab and anti-IL5 medications are currently included for use in patients with severe asthma, including children and adolescents, by several international asthma guidelines. The National Heart, Lung and Blood Institute’s Expert Panel 3 (NHLBI EPR3) guideline recommends the use of omalizumab as adjunctive therapy in patients above 12 years who have atopic, severe and persistent asthma inadequately controlled with high-dose ICS and LABA therapy.
The Global Initiative for Asthma (GINA) 2017 update recommends phenotype-guided add-on treatment with omalizumab in patients above 6 years with severe allergic asthma with elevated IgE, and mepolizumab or reslizumab in patients above 12 years with eosinophilic asthma as step 4 (medium dose ICS +LABA) therapy.
The Canadian Thoracic Society (CTS) recommends omalizumab in patients above 6 years with severe asthma that is inadequately controlled on high dose ICS and at least 1 other controller, sensitization to more than 1 perennial aeroallergen, and serum IgE levels between 30 and 1,300 IU/mL (6–11 years) or 30–700 IU/mL in patients above 12 years. The CTS also recommends anti-IL5 therapies in adults with severe eosinophilic corticosteroid-dependent asthma in an attempt to decrease or withdraw oral corticosteroids (OCS).
Benefits ‘at best Incremental’
Omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab are currently the five US FDA-approved monoclonal antibodies that affect the pathways involved in either allergic or type 2 inflammatory phenotypes of asthma. Presently, there are no head to head randomized or observational trials to study the comparative clinical effectiveness of these mAbs. Estimates from Cochrane meta-analyses showed that all five drugs reduced the annual exacerbation rate by about 50% with overlapping confidence intervals. The average improvement for four of the drugs, compared with a placebo, is modest and none of them reach the minimally important difference, although all were statistically significant. Dupilumab had the largest reduction in exacerbations and benralizumab the smallest, according to a meta-analysis by the Institute for Clinical and Economic Review (ICER), an independent non-profit research organisation. The risk for serious adverse events was low for all five drugs. The only consistent and common adverse event was injection-site reactions. The dosing schedule varies between the drugs. Dupilumab is given every two weeks, omalizumab is given every two to four weeks, mepolizumab and reslizumab are given every four weeks, and after the first three doses, benralizumab is given every eight weeks.
Notably, none of the drugs prevented most exacerbations requiring systemic corticosteroids or improved average daily quality of life to a degree considered clinically significant. Thus, the overall health benefit for all five drugs is at best incremental, notes ICER report.
“Unfortunately, the currently available biologics have not been shown to have disease-modifying properties for asthma,” comments Dr Nish, who is also the President of Northeast Georgia Physicians Group (NGPG) — Allergy and Asthma, GA. Studies have shown that asthma returns to its previous state of inflammation and pathology over time once the biologics are stopped, he adds.
The long-term safety and effectiveness of these drugs, however, is yet to be established particularly in older patients. For omalizumab and mepolizumab, long-term extension trials and real-world experience provide supportive but uncontrolled evidence. Response to therapy is yet to be well-defined to help guide patients and clinicians in deciding when to stop one therapy and consider switching to another.
At what cost?
Biologics comes with high treatment costs. Analysis indicate that biologic agents provide gains in quality-adjusted survival over the standard of care alone. Exacerbation reductions and chronic oral steroid reductions are potentially the most influential benefit associated with biologic therapy.
A survey by the Asthma and Allergy Foundation of America involving 805 Americans living with asthma, including 185 with severe, uncontrolled asthma, found that an average of 82% chose effectiveness as a key criterion while an average of 52% cited cost as a key criterion for selecting a therapy.
Patients report that their asthma prevents them from living the life that they want to live, besides impacting their loved ones. They also fear the side effects of corticosteroids and want to minimize the use of both systemic and inhaled corticosteroids as much as possible.
Given the high cost of these therapies, GINA recommends the use of biologics in patients whose asthma is refractory or relatively refractory to conventional inhaled therapies.
Biologics are also indicated for eosinophilic asthma. Eosinophils are part of the immune response to parasitic infections. It is unknown if the therapies that decrease eosinophil counts will affect patients’ ability to fight such infections. Current guidelines recommend that physicians treat patients for existing parasitic infections prior to initiating anti IL-5 therapy.
Researchers call for designing a large, pragmatic trial comparing all available drugs in order to clarify whether or not there are clinically important differences between the drugs.