Omalizumab (Xolair) may normalise IgE production rate in patients with moderate-to-severe atopic asthma
Philip Lowe[1], Stacey Tannenbaum[2], Aurelie Gautier[1]
[1]Novartis Pharma AG, 4002 Basel, Switzerland; [2]Novartis Pharmaceuticals Inc, East Hanover, New Jersey, USA
Objectives: Long-term anti-IgE therapy may attenuate the excess IgE expression observed in atopic individuals.
Methods: We investigated and quantified the timescale over which IgE production could be normalised using a direct binding model incorporating both dissociation constants and kinetic parameters for omalizumab, IgE and omalizumab-IgE complexes. This was written into a nonlinear mixed effect PK/PD model accounting for inter- and intra-patient variability. Input data were total serum omalizumab (sum of free and complex), free and total IgE from 1682 individuals with allergic asthma or rhinitis in four clinical studies of omalizumab. Two versions of the model were fitted: one with constant parameters; the other where IgE production rate could change over time. Normal IgE production was defined as 264 µg/day[1].
Results: Each model allowed relatively precise parameter estimation (maximum residual error, 25% coefficient of variation [CV]). The time-changing IgE production model gave a highly significant 2067-point decrease in log-likelihood objective function versus the constant IgE expression version. The estimated mean initial IgE production rate was 1840 µg/day (inter-patient CV, 29%). In control patients, IgE production appeared to increase slowly at an average rate of 2.4 ± 2.5% per year. IgE production rate decreased in omalizumab-treated patients and was projected to stabilise, ultimately, at 132 µg/day (168% CV). The apparent half-life of this change was approximately 1.5 years, providing a testable hypothesis that atopic patients may achieve normal IgE expression after 3-4 half-lives.
Conclusions: PK/PD models based on total and free IgE data suggest that, over the long term, omalizumab may be able to reduce IgE production towards normal (non-atopic) rates.
References:
[1] Waldmann TA, Lio A, Ogawa, M, et al J Immunol 1976; 117: 1139-44.