Investigational agents for asthma
- Richard J Martin, MD
Richard J Martin, MD
- Professor of Medicine
- University of Colorado Denver, School of Medicine
- Section Editors
- Bruce S Bochner, MD
Bruce S Bochner, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Adult Allergy; Asthma
- Samuel M Feinberg Professor of Medicine
- Northwestern University Feinberg School of Medicine
- Robert A Wood, MD
Robert A Wood, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Pediatric Allergy
- Professor of Pediatrics
- Johns Hopkins University School of Medicine
The standard treatment of patients with asthma is based upon trigger avoidance, bronchodilation, and anti-inflammatory therapy. Beta agonists, inhaled and systemic glucocorticoids, leukotriene modifiers, omalizumab, and, to a lesser extent, methylxanthines and anticholinergics all have a role in the conventional treatment of asthma. However, some patients do not achieve adequate control of their asthma with conventional therapy or experience adverse effects with conventional agents. Ongoing research is attempting to identify more effective and less toxic agents to control asthma.
Investigational approaches to asthma management, both promising and unsuccessful, will be reviewed here. Standard treatment regimens for asthma and complementary, alternative, and integrative approaches are discussed separately. (See "An overview of asthma management" and "Complementary, alternative, and integrative therapies for asthma".)
PROSTAGLANDIN D2 RECEPTOR ANTAGONIST
Prostaglandins are one of the major groups of metabolites (along with thromboxanes and leukotrienes) derived from arachidonic acid (figure 1). Prostaglandin D2 (PGD2) is the predominant prostaglandin produced by mast cells and is also produced by Th2 lymphocytes and dendritic cells. It has bronchoconstrictive and chemokinetic effects that may contribute to asthma pathogenesis, such as being a potent eosinophil chemoattractant. PGD2 acts on the PGD2 receptor 2 (DP2 receptor) on mast cells, eosinophils, and basophils. The DP2 receptor mediates migration of Th2 lymphocytes, delays Th2 cell apoptosis and stimulation of Th2 cells to produce interleukin-4 (IL-4), IL-5, and IL-13 among other effects. (See "Pathogenesis of asthma", section on 'Early and late phase reactions'.)
Fevipiprant is an investigational DP2 receptor antagonist that was assessed in a clinical trial of 61 patients with moderate-to-severe persistent asthma and an elevated sputum eosinophil count (≥2 percent) . The participants were randomly assigned to fevipiprant 225 mg or placebo orally twice a day for 12 weeks. The sputum eosinophil percentage decreased significantly from an initial geometric mean of 5.4 (95% CI 3.1-9.6) to 1.1 (95% CI 0.7-1.9) in the fevipiprant group and from 4.6 (95% CI 2.5-8.7) to 3.9 (95% CI 2.3-6.7) in the placebo group. Symptoms were assessed using the ACQ-7 questionnaire and were not different between groups. The quality of life questionnaire AQLQ score showed improvement in the fevipiprant group. A borderline benefit was noted in postbronchodilator, but not prebronchodilator, spirometry. No deaths or serious adverse events were reported. Further study is needed to explore the effects of fevipiprant on lung function and asthma exacerbations.
Several biologic agents targeting steps in the cascade of cytokines implicated in asthma inflammation have been developed in hopes of ameliorating the inflammation that underlies chronic asthma. A novel glucocorticoid receptor agonist approaches immunomodulation in a different way, by activating the glucocorticoid receptor, but possibly without the usual adverse effects of traditional glucocorticoids. (See "Pathogenesis of asthma", section on 'Airway inflammation'.)
- Gonem S, Berair R, Singapuri A, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2016; 4:699.
- Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008; 178:1002.
- Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 2013; 132:1086.
- Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med 2016; 111:21.
- 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.
- Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; 388:2115.
- FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 388:2128.
- Gauvreau GM, Boulet LP, Cockcroft DW, et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med 2011; 183:1007.
- Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088.
- Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132:567.
- Hanania NA, Korenblat P, Chapman KR, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med 2016; 4:781.
- Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013; 41:330.
- Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368:2455.
- Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388:31.
- Gauvreau GM, O'Byrne PM, Boulet LP, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014; 370:2102.
- Krug N, Hohlfeld JM, Kirsten AM, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med 2015; 372:1987.
- Gauvreau GM, Boulet LP, Leigh R, et al. A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses. Am J Respir Crit Care Med 2015; 191:161.
- Reiter J, Demirel N, Mendy A, et al. Macrolides for the long-term management of asthma--a meta-analysis of randomized clinical trials. Allergy 2013; 68:1040.
- Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343.
- Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest 2007; 132:1962.
- Martin RJ, Kraft M, Chu HW, et al. A link between chronic asthma and chronic infection. J Allergy Clin Immunol 2001; 107:595.
- Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008; 177:148.
- Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68:322.
- Kew KM, Undela K, Kotortsi I, Ferrara G. Macrolides for chronic asthma. Cochrane Database Syst Rev 2015; :CD002997.
- Evans DJ, Cullinan P, Geddes DM. Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002987.
- Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697.
- Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179:549.
- Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008; 63:584.
- Vrugt B, Wilson S, Bron A, et al. Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. Eur Respir J 2000; 15:478.
- Corrigan CJ, Shiner RJ, Shakur BH, Ind PW. Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy. Clin Exp Allergy 2005; 35:579.
- Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000; :CD000391.
- Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials. Respir Med 1998; 92:1059.
- Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study. Ann Intern Med 1991; 114:353.
- Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma. Thorax 1991; 46:936.
- Vallerand H, Cossart C, Milosevic D, et al. Fatal pneumocystis pneumonia in asthmatic patient treated with methotrexate. Lancet 1992; 339:1551.
- Evans DJ, Cullinan P, Geddes DM. Gold as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002985.
- Evans DJ, Cullinan P, Geddes DM. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002993.
- Ying S, Khan LN, Meng Q, et al. Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 in asthmatics. Eur Respir J 2003; 22:207.
- Coren ME, Rosenthal M, Bush A. The use of cyclosporin in corticosteroid dependent asthma. Arch Dis Child 1997; 77:522.
- Sato H, Ogawa K, Kojo Y, et al. Development of cyclosporine A-loaded dry-emulsion formulation using highly purified glycerol monooleate for safe inhalation therapy. Int J Pharm 2013; 448:282.
- Schwarz YA, Kivity S, Ilfeld DN, et al. A clinical and immunologic study of colchicine in asthma. J Allergy Clin Immunol 1990; 85:578.
- Fish JE, Peters SP, Chambers CV, et al. An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Am J Respir Crit Care Med 1997; 156:1165.
- Dewey A, Dean T, Bara A, et al. Colchicine as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2003; :CD003273.
- Roberts JA, Gunneberg A, Elliott JA, Thomson NC. Hydroxychloroquine in steroid dependent asthma. Pulm Pharmacol 1988; 1:59.
- Charous BL. Open study of hydroxychloroquine in the treatment of severe symptomatic or corticosteroid-dependent asthma. Ann Allergy 1990; 65:53.
- Charous BL. Effectiveness of long-term treatment of severe asthma with hydroxychloroquine (HCQ). Ann N Y Acad Sci 1991; 629:432.
- Mazer BD, Gelfand EW. An open-label study of high-dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991; 87:976.
- Landwehr LP, Jeppson JD, Katlan MG, et al. Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma. Chest 1998; 114:1349.
- Vrugt B, Wilson S, van Velzen E, et al. Effects of high dose intravenous immunoglobulin in two severe corticosteroid insensitive asthmatic patients. Thorax 1997; 52:662.
- Niggemann B, Leupold W, Schuster A, et al. Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma. Clin Exp Allergy 1998; 28:205.
- Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999; 103:810.
- Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin. J Allergy Clin Immunol 1999; 103:421.
- Ballow M. Is steroid-dependent asthma a disease treatable with intravenous immunoglobulin? Clin Immunol 1999; 91:123.
- Berlow BA, Liebhaber MI, Dyer Z, Spiegel TM. The effect of dapsone in steroid-dependent asthma. J Allergy Clin Immunol 1991; 87:710.
- Dewey A, Bara A, Dean T, Walters H. Dapsone as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2002; :CD003268.
- Enright PL, McNally JF, Souhrada JF. Effect of lidocaine on the ventilatory and airway responses to exercise in asthmatics. Am Rev Respir Dis 1980; 122:823.
- She ZW, Liming JD, Fagan JB, et al. Inhibition of hypochlorous acid by lidocaine and native components of alveolar epithelial lining fluid. Am Rev Respir Dis 1991; 144:227.
- Hunt LW, Frigas E, Butterfield JH, et al. Treatment of asthma with nebulized lidocaine: a randomized, placebo-controlled study. J Allergy Clin Immunol 2004; 113:853.
- Hunt LW, Swedlund HA, Gleich GJ. Effect of nebulized lidocaine on severe glucocorticoid-dependent asthma. Mayo Clin Proc 1996; 71:361.
- Koyama N, Kinsella MG, Wight TN, et al. Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells. Circ Res 1998; 83:305.
- Li CM, Newman D, Khosla J, Sannes PL. Heparin inhibits DNA synthesis and gene expression in alveolar type II cells. Am J Respir Cell Mol Biol 2002; 27:345.
- Lever R, Page C. Glycosaminoglycans, airways inflammation and bronchial hyperresponsiveness. Pulm Pharmacol Ther 2001; 14:249.
- Diamant Z, Timmers MC, van der Veen H, et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med 1996; 153:1790.
- Vancheri C, Mastruzzo C, Armato F, et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 2001; 108:703.
- Ceyhan B, Celikel T. Effect of inhaled heparin on methacholine-induced bronchial hyperreactivity. Chest 1995; 107:1009.
- Denning DW, O'Driscoll BR, Powell G, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009; 179:11.
- Matsuoka H, Niimi A, Matsumoto H, et al. Specific IgE response to trichophyton and asthma severity. Chest 2009; 135:898.
- Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol 2014; 134:33.
- PROSTAGLANDIN D2 RECEPTOR ANTAGONIST
- BIOLOGIC AGENTS
- Anti-IgE agents
- Anti-IL-2R antibody
- Anti-IL-5 therapy
- Anti-IL-13 antibodies
- Anti-lL-4 receptor alpha subunit antibody
- Anti-thymic stromal lymphopoietin
- GATA3-specific DNAzyme
- Novel glucocorticoid receptor agonist
- IMMUNOMODULATORY AGENTS WITH SIGNIFICANT LIMITATIONS
- Macrolide antibiotics
- Anti-TNF-alpha agents
- NEBULIZED AGENTS
- Nebulized lidocaine
- Nebulized heparin
- ANTIFUNGAL AGENTS
- SUMMARY AND RECOMMENDATIONS