Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma.
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 alpha 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 approximately 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 x 10(3)/microL; 24 hours postdose, 0.01 +/- 0.0 x 10(3)/microL); 94.0% of subjects receiving >or=0.03 mg/kg exhibited levels between 0.00 x 10(3)/microL and 0.01 x 10(3)/microL. 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 microg/L (baseline) to 10.3 +/- 7.0 microg/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 approximately 5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased approximately 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.


CONCLUSIONS
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.
Busse
William W
WW
University of Wisconsin School of Medicine and Public Health, Madison, Wis., USA.
Katial
Rohit
R
Gossage
David
D
Sari
Suha
S
Wang
Bing
B
Kolbeck
Roland
R
Coyle
Anthony J
AJ
Koike
Masamichi
M
Spitalny
George L
GL
Kiener
Peter A
PA
Geba
Gregory P
GP
Molfino
Nestor A
NA
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D002452:Cell Count; D047150:Eosinophil Cationic Protein / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D053666:Interleukin-5 Receptor alpha Subunit / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012129:Respiratory Function Tests
D000911:Antibodies, Monoclonal; D053666:Interleukin-5 Receptor alpha Subunit; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D002097:C-Reactive Protein; D047150:Eosinophil Cationic Protein