Biologic medications are a class of therapeutic agents derived from living organisms or genetically engineered proteins. These medications target specific molecules in the body responsible for immune responses and represent a paradigm shift in the care of patients asthma. Unlike traditional asthma medications, which broadly suppress inflammation in the airways, biologics work by neutralizing specific inflammatory pathways resulting in symptomatic improvement, reduction in asthma exacerbations, and reduction in oral corticosteroids. Since the approval of the first biologic medication for asthma, omalizumab, several medications have gained FDA approval and a considerable literature base has been built around their efficacy. We have listed a selection of landmark trials which represent important breakthroughs in understanding about the biology of severe asthma. Please note: this is by no means a comprehensive list. We hope this provides Asthma Center users a framework for further literature review.
Omalizumab
Mechanism of action: omalizumab is a recombinant humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE)
Year of FDA approval: 2003
FDA-approved indications:
1. adults and pediatric patients 6 years of age and older with moderate to severe asthma with a positive skin test or in vitro sensitization to a perennial aeroallergen and whose symptoms are inadequately controlled with ICS
2. add-on maintenance treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) in adults 18 years of age or older with inadequate response to nasal corticosteroids
3. adults and adolescents 12 years of age or older with chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine treatment
Medication dosing: Administered subcutaneously every 2 to 4 weeks; the dose and frequency depend on serum IgE levels and body weight
Landmark trials:
Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108:184–190
Ayres JG, Higgins B, Chilvers ER, Ayre G, Blogg M, Fox H. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma. Allergy 2004;59:701–708
Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, Fox H, Surrey K. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004;59:709–717
Holgate ST, Chuchalin AG, Hebert J, Lotvall J, Persson GB, Chung KF, Bousquet J, Kerstjens HA, Fox H, Thirlwell J et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004;34:632–638
Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard tehrapy: a randomized controlled trial. Ann Intern Med 2011;154:573-82
Mepolizumab
Mechanism of action: mepolizumab is a humanized IgG1κ monoclonal antibody that binds and inhibits IL-5
Year of FDA approval: 2015
FDA-approved indications:
1. add-on maintenance treatment of adults and pediatric patients 6 years of age and older with severe eosinophilic asthma
2. add-on maintenance treatment of adults 18 years of age and older with chronic rhinosinusitis with nasal polyps (CRSwNP)
3. adult patients with eosinophilic granulomatosis with polyangiitis (EGPA)
4. treatment of adult and pediatric patients 12 years of age and older with hypereosinophilic syndrome (HES) for 6 months or longer without an identifiable non-hematologic secondary cause
Medication dosing: Administered subcutaneously every 4 weeks; the dose depends on indication and age group
Landmark trials:
Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176:1062-1071
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.
Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM: Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993.
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-659.
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014;371:1198–1207
Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-1197.
Reslizumab
Mechanism of action: reslizumab is a humanized IgG4κ monoclonal antibody that binds and inhibits IL-5
Year of FDA approval: 2016
FDA-approved indications:
1. add-on maintenance treatment of adults 18 years of age or older with severe eosinophilic asthma
Medication dosing: Administered intravenously every 4 weeks; the dose is 3mg/kg via infusion given over 20-50 minutes
Landmark trials:
Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, Wilkins HJ, Henkel T, Nair P; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011;184:1125-1132
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O’Brien C, Korn S. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015;3:355–366
Benralizumab
Mechanism of action: benralizumab is a humanized IgG1κ monoclonal antibody that inhibits IL-5 activity by binding to the alpha subunit of the human IL-5 receptor
Year of FDA approval: 2017
FDA-approved indications:
1. add-on maintenance treatment of patients 12 years of age and older with severe eosinophilic asthma
2. treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA)
Medication dosing: Administered subcutaneously 30 mg every 4-8 weeks; the dose depends on indication and age group
Landmark trials:
Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V et al: Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 2013, 132:1086-1096 e1085.
Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, Gossage DL, Ward CK, Wu Y, Wang B et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014;2:879–890
FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S et al. Benralizumab, an anti-interleukin-5 receptor alpha 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;388:2128–2141
Bleeker 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 2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;388:2115-27
Ferguson GT, FitzGerald JM, Bleecker ER, Laviolette M, Bernstein D, LaForce C, Mansfield L, Barker P, Wu Y, Jison M et al. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2017;5:568-576.
Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376:2448–2458
Dupliumab
Mechanism of action: dupilumab is a human IgG4 monoclonal antibody that binds to the alpha subunit of the human IL-4 receptor and inhibits IL-4 and IL-13 signaling
Year of FDA approval: 2018
FDA-approved indications:
1. add-on maintenance treatment of adult and pediatric patients 6 years and older with moderate to severe eosinophilic asthma or oral corticosteroid-dependent asthma
2. add-on maintenance treatment in adult and pediatric patients 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP)
3. treatment of adult and pediatric patients 6 months and older with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable
4. treatment of adult and pediatric patients 1 year of age or older, weighing at least 15 kg, with eosinophilic esophagitis
5. treatment of adult patients with prurigo nodularis
6. add-on maintenance therapy of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype
Medication dosing: Administered subcutaneously; the dose and frequency depend on indication and age group
Landmark trials:
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013;368:2455–2466
Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN 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 beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31–44
Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, Ford L, Sher L, FitzGerald JM et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378:2486–2496
Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, Zhu H, Hamilton JD, Swanson BN, Khan A et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018;378:2475–2485
Tezepelumab
Mechanism of action: tezepelumab is a human IgG2λ monoclonal antibody that binds and inhibits thymic stromal lymphopoietin (TSLP)
Year of FDA approval: 2021
FDA-approved indications:
1. add-on maintenance treatment of adult and pediatric patients 12 years of age or older with severe asthma
Medication dosing: Administered subcutaneously 210 mg once every 4 weeks
Landmark trials:
Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, van der Merwe R. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017;377:936–946
Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, Brightling CE, Griffiths JM, Hellqvist Å, Bowen K, Kaur P, Almqvist G, Ponnarambil S, Colice G. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med 2021;384:1800-1809
Wechsler ME, Menzies-Gow A, Brightling CE, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomized, placebo-controlled, phase 3 study. Lancet Respir Med;10:650-60