Asthma and lower airway disease
Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma

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Background

Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis.

Objective

To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor α chain.

Methods

Single, escalating, intravenous doses (0.0003-3 mg/kg) of MEDI-563 were administered to subjects with mild atopic asthma (n = 44) over ∼3 to 30 minutes in this open-label study. Pulmonary function, symptom scores, adverse events, MEDI-563 pharmacokinetics, and levels of C-reactive protein (CRP), IL-6, eosinophil cationic protein (ECP), and eosinophils were evaluated.

Results

Mean peripheral blood (PB) eosinophil levels decreased in a dose-dependent fashion (baseline ± SD, 0.27 ± 0.2 × 103/μL; 24 hours postdose, 0.01 ± 0.0 × 103/μL); 94.0% of subjects receiving ≥0.03 mg/kg exhibited levels between 0.00 × 103/μL and 0.01 × 103/μL. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg, respectively. ECP levels were reduced from 21.4 ± 17.2 μg/L (baseline) to 10.3 ± 7.0 μg/L (24 hours postdose). The most frequently reported adverse events were reduced white blood cell counts (34.1%), nasopharyngitis (27.3%), and increased blood creatine phosphokinase (25.0%). Mean C-reactive protein levels increased ∼5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased ∼3.9-fold to 4.7-fold at 6 to 12 hours postdose, respectively. Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg.

Conclusion

Single escalating doses of MEDI-563 had an acceptable safety profile and resulted in marked reduction of PB eosinophil counts within 24 hours after dosing.

Section snippets

Subjects

Adults (age 18-45 years) with mild atopic asthma (nighttime symptoms ≤1/wk and daytime symptoms <1/d, FEV1 or peak expiratory flow ≥80% of predicted, and peak expiratory flow variability ≤30%) were eligible. A methacholine provocation dose causing 20% decrease in FEV1 (PC20) of ≤8 mg/mL was required during the first visit (day −14 to −7) or documented within 6 months previously. Women were eligible if postmenopausal, surgically sterile, or willing to use birth control for the duration of the

Demographics and baseline characteristics

Of the 44 subjects enrolled, 39 (88.6%) completed the study. Three subjects withdrew consent (0.1 mg/kg, n = 1; 1 mg/kg, n = 1; 3 mg/kg, n = 1), and 2 subjects (0.0003 mg/kg) were lost to follow-up. Baseline characteristics were generally comparable among all treatment groups (Table I).

Three additional subjects were added to the 1 mg/kg group (n = 9) when half of the 6 subjects in the 3 mg/kg group experienced a cluster of AEs after infusion with MEDI–563 (see Safety profile). All of these

Discussion

MEDI-563 produced depletion of circulating PB eosinophil levels within 24 hours at all doses administered. This effect persisted for at least 2 to 3 months in subjects dosed in the 0.03 mg/kg to 3 mg/kg range. Basophil counts were not reported in this study because of the known difficulties of obtaining a reliable measurement using standard techniques.22 Future studies will use flow cytometry to assess changes in basophils counts. In addition to the biological effect observed, no deterioration

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    Supported by MedImmune, LLC, Gaithersburg, Md, and Biowa, Inc, Princeton, NJ.

    Disclosure of potential conflict of interest: W. W. Busse is a consultant for and is on the advisory board of Altair, GlaxoSmithKline, Merck, Wyeth, Pfizer, Centocor, Amgen, UCB, Johnson & Johnson, Novartis, AstraZeneca, Eisai, TEVA, CompleWare, KaloBios, Boehringer Ingelheim, and Sandoz and has received research support from NIH-NIAID, NIH-NHLBI, Novartis, Centocor, GlaxoSmithKline, MedImmune, and Ception. D. Gossage, S. Sari, B. Wang, R. Kolbeck, A. J. Coyle, G. P. Geba, and N. A. Molfino are employed by MedImmune. P. A. Kiener was employed by MedImmune at the time of the study conduct. M. Koike and G. L. Spitalny are employed by Biowa, Inc. R. Katial declares no conflict of interest.

    S. Sari is currently employed by Emergent BioSolutions, Rockville, Md.

    ∗∗

    P. A. Kiener is currently employed by Zyngenia, Inc, Gaithersburg, Md.

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