Abstract
Introduction
The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥30 IU/mL.
Methods
Subjects with atopy and/or baseline IgE ≥30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made.
Results
MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events.
Conclusions
The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab.
Funding
MedImmune.
Trial registration
ClinicalTrials.gov identifier, NCT01544348.
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References
Thomsen SF. Atopic dermatitis: natural history, diagnosis, and treatment. ISRN Allergy. 2014;2014:354250.
Velling P, Skowasch D, Pabst S, Jansen E, Tuleta I, Grohe C. Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy. Eur J Med Res. 2011;16:407–10.
Marth K, Focke-Tejkl M, Lupinek C, Valenta R, Niederberger V. Allergen peptides, recombinant allergens and hypoallergens for allergen-specific immunotherapy. Curr Treat Options Allergy. 2014;1:91–106.
Baiardini I, Braido F, Brandi S, Canonica GW. Allergic diseases and their impact on quality of life. Ann Allergy Asthma Immunol. 2006;97:419–28.
Gould HJ, Sutton BJ, Beavil AJ, et al. The biology of IgE and the basis of allergic disease. Annu Rev Immunol. 2003;21:579–628.
Chang TW, Wu PC, Hsu CL, Hung AF. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol. 2007;93:63–119.
Wu LC, Zarrin AA. The production and regulation of IgE by the immune system. Nat Rev Immunol. 2014;14:247–59.
Gounni AS, Lamkhioued B, Ochiai K, et al. High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature. 1994;367:183–6.
Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125:S73–80.
Novak N, Allam JP, Hagemann T, et al. Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol. 2004;114:364–70.
Schroeder JT, Bieneman AP, Xiao H, et al. TLR9- and FceRI-mediated responses expression dendritic cells by down-regulating receptor oppose one another in plasmacytoid. J Immunol. 2005;175:5724–31.
MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol. 1997;158:1438–45.
Saini SS, MacGlashan DW Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol. 1999;162:5624–30.
Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004;114:527–30.
Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol. 2003;112:1147–54.
Holgate S, Buhl R, Bousquet J, Smith N, Panahloo Z, Jimenez P. The use of omalizumab in the treatment of severe allergic asthma: a clinical experience update. Respir Med. 2009;103:1098–113.
Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, Holgate S. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2:525–36.
Novartis. Omalizumab EU product information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000606/WC500057298.pdf. Accessed 5 Dec 2014.
Maurer M, Rosen K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368:924–35.
Mortensen DL, Prabhu S, Stefanich EG, et al. Effect of antigen binding affinity and effector function on the pharmacokinetics and pharmacodynamics of anti-IgE monoclonal antibodies. MAbs. 2012;4:724–31.
Putnam WS, Li J, Haggstrom J, et al. Use of quantitative pharmacology in the development of HAE1, a high-affinity anti-IgE monoclonal antibody. AAPS J. 2008;10:425–30.
Arm JP, Bottoli I, Skerjanec A, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy. 2014;44:1371–85.
Cohen ES, Dobson CL, Kack H, et al. A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. MAbs. 2014;6:756–64.
GINA Report. Global strategy for asthma management and prevention. 2007. http://www.ginasthma.org.
Meno-Tetang GM, Lowe PJ. On the prediction of the human response: a recycled mechanistic pharmacokinetic/pharmacodynamic approach. Basic Clin Pharmacol Toxicol. 2005;96:182–92.
Hayashi N, Tsukamoto Y, Sallas WM, Lowe PJ. A mechanism-based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab. Br J Clin Pharmacol. 2007;63:548–61.
Cohen ES, Dobson CL, Kack H, et al. A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. MAbs. 2014;6:756–64.
Lowe PJ, Tannenbaum S, Gautier A, Jimenez P. Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma. Br J Clin Pharmacol. 2009;68:61–76.
Lowe PJ, Renard D. Omalizumab decreases IgE production in patients with allergic (IgE-mediated) asthma; PKPD analysis of a biomarker, total IgE. Br J Clin Pharmacol. 2011;72:306–20.
Malveaux FJ, Conroy MC, Adkinson NF Jr, Lichtenstein LM. IgE receptors on human basophils. Relationship to serum IgE concentration. J Clin Invest. 1978;62:176–81.
Borkowski TA, Jouvin MH, Lin SY, Kinet JP. Minimal requirements for IgE-mediated regulation of surface Fc epsilon RI. J Immunol. 2001;167:1290–6.
MacGlashan D Jr, Xia HZ, Schwartz LB, Gong J. IgE-regulated loss, not IgE-regulated synthesis, controls expression of FcepsilonRI in human basophils. J Leukoc Biol. 2001;70:207–18.
Bang LM, Plosker GL. Omalizumab: a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183–99.
Acknowledgments
Funding for this study and article processing charges were provided by MedImmune. All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Medical writing support was provided by Ruth Steer, PhD, QXV Communications (an Ashfield business, part of UDG Healthcare plc), Macclesfield, UK, which was fully funded by MedImmune.
The authors would like to thank the investigators at the study sites, as well as the subjects who participated in this study. We would like to thank Dr. Chad Oh and Dr. Bing Wang for developing the study protocol and Dr. Meina Liang for bioanalytical support. We would also like to thank Dr. Virginia Litwin for validation of and testing samples with the flow cytometric method, and Slava Inyushin and Kemal Balic for help with analysis of the data.
Disclosures
Dr. Eric Sheldon has been a principal investigator for clinical trials sponsored by MedImmune.
Drs. Birrell, Kell, Kim, Li and Schwickart, and Ms. Crouch and Parveen, are employees of MedImmune and own stock in AstraZeneca.
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.
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Sheldon, E., Schwickart, M., Li, J. et al. Pharmacokinetics, Pharmacodynamics, and Safety of MEDI4212, an Anti-IgE Monoclonal Antibody, in Subjects with Atopy: A Phase I Study. Adv Ther 33, 225–251 (2016). https://doi.org/10.1007/s12325-016-0287-8
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DOI: https://doi.org/10.1007/s12325-016-0287-8