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.
University of Wisconsin School of Medicine and Public Health, Madison, Wis., USA.
William W
WW
Busse
Rohit
R
Katial
David
D
Gossage
Suha
S
Sari
Bing
B
Wang
Roland
R
Kolbeck
Anthony J
AJ
Coyle
Masamichi
M
Koike
George L
GL
Spitalny
Peter A
PA
Kiener
Gregory P
GP
Geba
Nestor A
NA
Molfino
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