Novel Therapies for Asthma

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asthmaBy David H. Broide, MD, ChB

Asthma is a very common airway disease affecting approximately 20 million individuals in the United States. For many patients with persistent asthma, asthma is well controlled with a regular controller medication, such as an inhaled corticosteroid, and an as-needed beta2-agonist inhaler for symptom relief.[1] Nevertheless, each year in the United States, there are still approximately 10 million acute attacks of asthma, 2 million asthma urgent care visits, 400,000 asthma hospitalizations, and 4000-5000 asthma deaths, underscoring the fact that asthma is still not well controlled in a large number of asthmatics.[2] Patients with severe asthma use a significant fraction of the $6.2 billion in annual direct cost expenditure on asthma in the United States.[3] The development of novel therapeutic options for these asthmatics would be a significant advance.

Rate of Successful Development of Novel Therapies for Human Disease

Although advances in biomedical research, such as the sequencing of the human genome, have provided an ever-expanding number of new, well-defined targets to consider as potential novel therapies for asthma, the overall success rate of developing novel therapies from successful proof of principal studies in animal models of disease to a safe and effective therapeutic product in human disease is still a significant hurdle to overcome. Recent studies have demonstrated that, for all diseases, the rate of successful development following successful proof of concept in an animal model to a US Food and Drug Administration (FDA)-approved human therapy is approximately 8%.[4] Thus the vast majority of therapies entering human clinical trials will fail human phase 1 safety studies (40% failure rate). Of those who pass, many fail human phase 2 small-scale efficacy studies (70% failure rate) or fail phase 3 large-scale efficacy studies (50% failure rate).[4] Therefore, it is important to keep in mind that a novel therapy showing promise in animal model studies has only an approximately 8% chance of becoming an FDA-approved product. Nevertheless, in the field of asthma, 2 new classes of novel therapeutics (anti-immunoglobulin [Ig]E and leukotriene inhibitors) have been successfully developed in the past decade.

Targeting Cytokines in Asthma

Cytokines are proteins that play an important role in how cells communicate with each other. As targeting the cytokine tumor necrosis factor (TNF) has been successful in the therapy of patients with rheumatoid arthritis, efforts in asthma have focused on identifying whether a key cytokine involved in disease pathogenesis could be identified in asthma as well. Although a large number of cytokines and growth factors have been detected in the airway in asthma, identifying which if any of these cytokines plays an important role in disease pathogenesis in humans has proven to be challenging. Both inflammatory cells in the airway, including T cells, mast cells, eosinophils, and macrophages, and structural cells in the airway, such as epithelium and smooth muscle cells, generate and respond to cytokine signals. Targeting interleukin (IL)-4 is an example of an anticytokine approach that showed great promise in asthma on the basis of growing knowledge of the importance of IL-4 as a switch factor for B cells to make IgE, as well as the knowledge of the ability of IL-4 to induce endothelial cells to express adhesion molecule vascular cell adhesion molecule (VCAM)-1, which binds to the counter-receptor VLA-4 expressed on eosinophils and mononuclear cells and thus assists in the localization of these proinflammatory cells in the airway in asthma.[5] Although initial phase 2 studies in asthma with a therapy to neutralize IL-4 in asthma showed significant promise,[5] subsequent large-scale phase 3 studies did not confirm this initial promise. These studies underscore the difficulty of translating a promising therapeutic target into an approved therapy in asthma.

Will Anti-TNF Be Effective in Asthma?

Increased levels of TNF are noted in the airways of patients with symptomatic asthma.[6] Recent placebo-controlled studies have investigated the effects of treatment with a soluble TNF-alpha receptor administered twice weekly in patients with refractory asthma.[7] Asthmatics who had received 10 weeks of treatment with a soluble TNF-alpha receptor had a significant increase in the concentration of methacholine required to provoke a 20% decrease in the forced expiratory volume in 1 second (FEV1), as well as a significant improvement in the asthma-related quality-of-life score and a 0.32-L increase in postbronchodilator FEV1. This report[7] and other recent studies[8,9] suggested that targeting TNF may be helpful in some subjects with asthma. However, at present, anti-TNF is not approved for the treatment of asthma, and further studies are needed to determine the safety and effectiveness of targeting TNF in asthma.

Anti-IL-5, Eosinophils, and Allergic Diseases

The presence of increased numbers of eosinophils in peripheral blood, sputum, and airways is a characteristic feature of asthma. The demonstration that the cytokine IL-5 is an eosinophil growth factor led to the development of therapies, such as anti-IL-5, to deplete eosinophils from the airways in patients with asthma and assess whether this change would improve symptoms in patients with asthma. However, in studies of mild asthmatics, anti-IL-5 did not inhibit the late-phase response to inhalation allergen challenge or airway hyperreactivity to methacholine.[10] Subsequently, 2 different doses of anti-IL-5 have been studied in subjects with severe persistent asthma who were also treated with oral corticosteroids or high doses of inhaled corticosteroids.[11] In these studies of anti-IL-5 in more severe asthmatics, the lower dose of anti-IL-5 had a trend toward transient early improvement in FEV1 24 hours after the anti-IL-5 was administered (P = .02 vs placebo). This effect was not sustained at any other timepoint in the 3-month study.[11] In addition, anti-IL-5 induced no significant changes in other clinical indexes of asthma disease activity, including asthma symptom scores, or asthma rescue medication use.[11] Subsequent studies have, however, demonstrated that anti-IL-5 reduces levels of airway remodeling in asthma.[12] The mechanism by which anti-IL-5 reduces levels of airway remodeling in asthma is considered to be due to anti-IL-5 reducing levels of eosinophil expression of the pro-remodeling cytokine transforming growth factor-beta in the airways in asthma.[12] Thus, novel therapies such as anti-IL-5 may not inhibit all aspects of the asthma phenotype, but may be important for selected aspects of asthma pathology, such as airway remodeling.

Should We Be Using Antibiotics to Treat Acute Exacerbations of Asthma?

Acute asthma exacerbations are characteristically triggered by viruses, especially rhinoviruses.[13] Thus, antibiotics are not part of the standard approach to treating asthma exacerbations. However, some investigators have challenged this prevailing practice and proposed that atypical bacterial infections, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, may be important factors in both acute exacerbations of asthma and chronic asthma.[14] A recent double-blind study in the United Kingdom assessed whether adding an antibiotic to standard treatment of an asthma exacerbation would improve the primary endpoints of the study, ie, asthma symptom scores or peak expiratory flow rate at day 10 after institution of antibiotic therapy at the start of the asthma exacerbation. The results of the study demonstrated that telithromycin, an antibiotic to which M pneumoniae and C pneumoniae are sensitive, had a statistically significant effect on reducing asthma symptoms, but did not improve peak expiratory flow rate. There was also a significant improvement in FEV1 in the telithromycin-treated group at day 14. Although these studies are interesting, the amount of improvement in asthma symptoms that the antibiotic conferred was very modest (43% reduction in symptoms with telithromycin vs 35% reduction in symptoms with placebo). Thus, at this time, antibiotics are still not indicated in the vast majority of acute exacerbations of asthma.

Targeting Allergic Rhinitis and Asthma With TLR9 Agonists

Studies have demonstrated that the innate immune system plays an important role in modulating the adaptive immune response to inhaled allergens. Activation of the innate immune system by DNA containing unmethylated CpG dinucleotides (CpG DNA) can inhibit allergic responses in mouse models of asthma and are, therefore, being considered as therapies for human asthma and allergy.[15,16] CpG DNA activates the innate immune response by binding to the toll-like receptor (TLR)9 expressed by plasmacytoid dendritic cells. Activation of TLR9 on dendritic cells induces expression of cytokines that inhibit the proallergic adaptive Th2 immune response. On the basis of these preclinical observations, phase 2 studies have investigated whether TLR9-directed vaccines can inhibit allergic responses in studies initially performed in ragweed-allergic subjects with Amb a 1 immunostimulatory oligonucleotide conjugate (AIC), which is a combination of the ragweed allergen protein Amb a 1 conjugated to the CpG DNA sequence that binds to TLR9. Subjects with ragweed-induced allergic rhinitis immunized with 6 injections of AIC before the first ragweed season demonstrated significant clinical improvement in rhinitis symptom scores during the ragweed season.[15] The clinical improvement in response to AIC persisted for 2 ragweed seasons, even though injections of AIC were only administered before the first ragweed season.[15] Subjects on AIC used less rescue allergy medications during the ragweed season compared with subjects on placebo. AIC suppressed the seasonal increase in Amb a 1-specific IgE antibody. Further large-scale studies are still needed to determine the efficacy and safety of AIC in treating subjects with allergic rhinitis and whether this approach will be effective in asthma. Studies of CpG DNA alone, as opposed to being conjugated to an allergen, have shown promise in mouse[16] and primate models[17] of allergen-induced asthma. However, CpG DNA administered by inhalation in humans with asthma did not inhibit the late-phase response to inhalation allergen challenge in mild asthmatics.[18]

Conclusion

A large number of novel targets have been identified in preclinical animal models of asthma that hold significant promise for the treatment of asthma. However, the high attrition rate of promising candidate targets once they enter human studies makes it likely that only a small fraction of the promising targets will prove to be effective and safe for the treatment of asthma.

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