R. Zhu*(1), Y. Zheng*(1), W. Putnam(1), J. Visich(1), T. Lu(1), J. Jin(1), M. Eisner(2), K. Rosén (3), J. Matthews(3), D.Z.D’Argenio(4), *These authors contributed equally to this work.
(1) Department of Clinical Pharmacology, Genentech, Inc. South San Francisco, CA, USA; (2) Department of Clinical Science Immunology, Genentech, Inc. South San Francisco, CA, USA; (3) Department of Clinical Science Respiratory, Genentech, Inc. South San Francisco, CA, USA; (4) Biomedical Simulations Resource (BMSR), University of Southern California, Los Angeles, CA, USA.
Objectives: Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-IgE agent indicated in the US for adults and adolescents (≥ 12 years of age) with moderate-to-severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids (ICS). The objective of this study was to use population-based efficacy modeling to quantitatively characterize the relationship between serum free IgE and pulmonary function (as measured by FEV1, forced expiratory volume in 1 sec) following treatment with omalizumab in asthma patients.
Methods: A population-based efficacy model linking serum free IgE level to FEV1 was developed to describe FEV1 responses. The model utilizes a single differential equation to describe FEV1 responses in both placebo and omalizumab groups. The model was developed using data from the EXTRA trial [1] in which severe allergic asthma patients received omalizumab or placebo (in addition to high-dose ICS and long-acting beta agonists (LABA), with or without additional controller medications) for 48 weeks [2]. The dosing was based on baseline IgE and body weight according to the omalizumab dosing table. Numerous covariates, including demographics, disease status, and baseline pharmacodynamic biomarkers, were evaluated in the modeling to explain the variability in the FEV1 response. The model was expanded to incorporate the effect of ICS on FEV1 using a direct-response model, and fitted to data from omalizumab Phase III pivotal trials [3,4] in asthma with time-varying ICS doses.
Results: Results from the IgE-FEV1 model confirmed the current omalizumab dosing rationale in asthma based on the mean target serum free IgE level of 25 ng/mL [5] and quantified the variability for the target. None of the covariates evaluated were significant in explaining the variability in the FEV1 response. The expanded model incorporating the ICS effects on FEV1 adequately described the data from omalizumab Phase III pivotal trials in asthma and confirmed the estimated target free IgE level from the original IgE-FEV1 model.
Conclusions: The population-based efficacy model presented provided useful insights into the relationships between serum free IgE level and pulmonary function (as measured by FEV1) in asthma patients. The modeling results provided a quantitative confirmation for the mean target free IgE level (25 ng/mL) for omalizumab treatment.
References:
[1] Hanania NA, Alpan O, et al. Omalizumab in severe allergic asthma in inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573-82.
[2] Zhu R, Zheng Y, et al. Population-Based Efficacy Modeling of Omalizumab in Patients with Severe Allergic Asthma Inadequately Controlled with Standard Therapy. AAPS J. 2013 Feb 15. [Epub ahead of print]
[3] Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:184-90.
[4] Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18:254-61.
[5] Hochhaus G, Brookman L, Fox H, Johnson C, Matthews J, Ren S, et al. Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opin. 2003;19:491-8.
Reference: PAGE 22 (2013) Abstr 2926 [www.page-meeting.org/?abstract=2926]
Poster: Other Drug/Disease Modelling