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Am. J. Respir. Crit. Care Med., Volume 160, Number 6, December 1999, 1816-1823

Interleukin-4 Receptor in Moderate Atopic Asthma
A Phase I/II Randomized, Placebo-controlled Trial

LARRY C. BORISH, HAROLD S. NELSON, MIGUEL J. LANZ, LORI CLAUSSEN, JAMES B. WHITMORE, JAN M. AGOSTI, and LESLIE GARRISON

Department of Medicine, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado; and Immunex Corporation, Seattle, Washington

Interleukin-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, expression of VCAM-1 on endothelium, mucin production, 15-lipoxygenase activity, and Th2 lymphocyte stimulation leading to the secondary synthesis of IL-4, IL-5, and IL-13. Soluble recombinant human IL-4 receptor (IL-4R; Nuvance; altrakincept) inactivates naturally occurring IL-4 without mediating cellular activation. Nebulized IL-4R has a serum half-life of approximately 1 wk. In this double-blind, placebo-controlled trial, 25 patients with moderate asthma requiring inhaled corticosteroids were randomly assigned to receive a single nebulized dose of IL-4R 1,500 µg, IL-4R 500 µg, or placebo after stopping inhaled corticosteroids. No drug-related toxicity was observed. Treatment with IL-4R produced significant improvement in FEV1 on Day 4 (1,500 µg versus placebo; p < 0.05) and in FEF25-75 on Days 2 and 4 (1,500 µg versus placebo; p < 0.05). Asthma symptom scores stabilized among patients treated with IL-4R 1,500 µg, despite abrupt withdrawal of corticosteroids, but not in the IL-4R 500 µg group or the placebo group (p < 0.05). Patients in the IL-4R 1,500 µg group also required significantly less beta 2-agonist rescue use (p < 0.05). Anti-inflammatory effects were further demonstrated by significantly reduced exhaled nitric oxide (p < 0.05). Conclusions: A single dose of IL-4R appears safe and effective in moderate asthma. The 1,500 µg dose appears as safe but significantly more effective than the 500 µg dose. Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, Garrison L. Interleukin-4 receptor in moderate atopic asthma: a phase I/II randomized, placebo-controlled trial.




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