Tratamiento del asma: la terapia biológica que viene

David Ramos Barbón

Resumen


Las técnicas de producción de anticuerpos monoclonales contra dianas específicas, y los procedimientos de biología molecular que facilitan la reducción su inmunogenicidad en sujetos humanos, han hecho posible el desarrollo en actual expansión de todo un universo de terapias basadas en una tecnología común, con un profundo impacto en prácticamente todas las especialidades médicas. La primera terapia basada en un anticuerpo monoclonal en llegar al campo respiratorio fue el omalizumab, aprobado por la European Medicines Agency (EMEA) en 2005. Tras una década amplia de experiencia, y también de lapso, llegan de forma inminente al campo de las enfermedades respiratorias nuevas terapias basadas en anticuerpos monoclonales. Como el omalizumab, las nuevas terapias hacen diana en  vías inmunobiológicos del asma, y algunas de ellas tendrán previsiblemente una indicación extendida a ciertos perfiles de EPOC. En conjunto, una porción apreciable de los sujetos que padecen asma grave refractaria al tratamiento máximo convencional resultarán beneficiados de forma clínicamente relevante. Sin embargo, debido a un conjunto de razones primariamente asociadas a nuestro conocimiento sobre vías inmunobiológicos y las limitaciones del mismo, la totalidad de los anticuerpos monoclonales en estado de comercialización, proceso de aprobación o desarrollo avanzado se concentra sobre el asma atópica y/o eosinofílica, quedando actualmente en un importante vacío de líneas de desarrollo el resto de las formas de asma grave refractaria. Asimismo, la entrada en el escenario terapéutico de los nuevos anticuerpos monoclonales generará nuevas cuestiones científico-clínicas. En el presente artículo de opinión, se ofrece una "instantánea" actual sobre estos diferentes aspectos.

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Referencias


Masoli M, Fabian D, Holt S, Beasley R; Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–78.

Global Strategy for the Diagnosis, Management, and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2016. Disponible en: http://goldcopd.org/.

Murray JF. The normal lung. Philadelphia: W. B. Saunders Company. 1986.

Schwartz RS. Paul Ehrlich’s magic bullets. N Engl J Med. 2004;350:1079–80.

Springer TA. César Milstein, the father of modern immunology. Nat Immunol. 2002;3:501–3.

White RA, Mason DW, Williams AF, Galfre G, Milstein C. T-lymphocyte heterogeneity in the rat: separation of functional subpopulations using a monoclonal antibody. J Exp Med. 1978;148:664–73.

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.

Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–73.

Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature. 1988;332:323–7.

Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112:1557–69.

Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ. Helper T cell diversity and plasticity. Curr Opin Immunol. 2012;24:297–302.

U.S. Food and Drug Administration 2003. Omalizumab Product Approval Information - Licensing Action. Disponible en: http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm093373.htm.

European Medicines Agency 2005. Xolair: EPAR - Procedural steps taken before authorisation. Disponible en: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000606/human_med_001162.jsp&mid=WC0b01ac058001d124.

European Medicines Agency 2005. Xolair: EPAR - Scientific Discussion. Disponible en: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000606/human_med_001162.jsp&mid=WC0b01ac058001d124.

Abraham I, Alhossan A, Lee CS, Kutbi H, MacDonald K. ‘Real-life’ effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review. Allergy. 2016;71:593–610.

Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–98.

Noonan M, Korenblat P, Mosesova S, Scheerens H, Arron JR, Zheng Y, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol. 2013;132:567–74.

Scheerens H, Arron JR, Zheng Y, Putnam WS, Erickson RW, Choy DF, et al. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge. Clin Exp Allergy. 2014;44:38–46.

Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330–8.

Brightling CE, Chanez P, Leigh R, O’Byrne PM, Korn S, She D, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692–701.

Staton TL, Choy DF, Arron JR. Biomarkers in the clinical development of asthma therapies. Biomark Med. 2016;10:165–76.

Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455–66.

Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, 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;doi:10.1016/S0140-6736(16)30307-5. [Epub ahead of print].

Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–84.

Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al.; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–207.

Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al.; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189–97.

Thompson CA. Mepolizumab approved as add-on long-term therapy for severe asthma. Am J Health Syst Pharm. 2015;72:2125.

Keating GM. Mepolizumab: First Global Approval. Drugs. 2015;75:2163–9.

Powell C, Milan SJ, Dwan K, Bax L, Walters N. Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev. 2015;7:CD010834.

Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2015;372:1777.

Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;doi:10.1016/S2213-2600(16)30031-5. [Epub ahead of print].

Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al.; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125–32.

Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, 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 Respir Med. 2015;3:355–66.

Markham A. Reslizumab: First Global Approval. Drugs. 2016;76:907–11.

Bjermer L, Lemière C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for Inadequately Controlled Asthma with Elevated Blood Eosinophil Levels: a Randomized Phase 3 Study. Chest. 2016;doi:10.1016/j.chest.2016.03.032. [Epub ahead of print].

Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 Study of Reslizumab in Patients with Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts. Chest. 2016;doi:10.1016/j.chest.2016.03.018. [Epub ahead of print].

Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086–96.

Ghazi A, Trikha A, Calhoun WJ. Benralizumab--a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma. Expert Opin Biol Ther. 2012;12:113–8.

Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct Pulmon Dis. 2006;1:39–47.

Bafadhel M, Saha S, Siva R, McCormick M, Monteiro W, Rugman P, et al. Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. Respiration. 2009;78:256–62.

Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184:662–71.

Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356:1480–5.

Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax. 2005;60:193–8.

Lemière C, Ernst P, Olivenstein R, Yamauchi Y, Govindaraju K, Ludwig MS, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol. 2006;118:1033–9.

Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol. 2007;119:1043–52.

Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–19.

Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–24.

Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–9.

Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294–302.

Ramos Barbón D. De la biología a la clínica. Asma. Arch Bronconeumol. 2007;43 Supl 2:3–14.


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