Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma.
BACKGROUND
Very late antigen (VLA-4) antagonists have been proposed as potential therapies for diseases in which cell recruitment and accumulation are causative. Asthma, which is characterized by airway inflammation involving the accumulation of eosinophils and mononuclear cells, is one such disease.


OBJECTIVE
We sought to assess the effect of IVL745, a VLA-4 antagonist, on the early and late asthmatic response (LAR) and on markers of airway inflammation after allergen inhalation.


METHODS
The study was of a placebo-controlled, double-blind, randomized, 2-way crossover design. Sixteen subjects with mild-to-moderate asthma controlled with short-acting beta2-agonists only and with a LAR to inhaled allergen participated in the study. At one treatment period they took 20 mg of IVL745 and one treatment period placebo. Both treatments were taken twice daily for 7 days, with a single dose on day 8. Treatments were separated by a washout period of at least 2 weeks. On day 7 of each treatment period, sputum was induced and collected, and exhaled nitric oxide (NO) was measured. On day 8, an inhaled bolus allergen challenge was performed, and blood was taken for pharmacokinetics. On day 9, exhaled NO was measured, and a methacholine challenge was done. On day 10, sputum was induced and collected. Adverse events, peak expiratory flow (PEF), use of short-acting beta2-agonists, and asthma symptoms were recorded daily throughout the study.


RESULTS
There was no statistically significant difference between IVL745 and placebo in the effect on the LAR after allergen challenge, as measured by the area under the curve of the percentage change in FEV1 from the prechallenge baseline (mean [SEM], -81.99 [18.80] after IVL745 and -72.58 [21.29] after placebo; 95% CI of difference, -36 to 16.8; P = .46) or by the maximum percentage change from the prechallenge baseline (mean [SEM], -23.44 [4.73] after IVL745 and -21.30 [5.17] after placebo; 95% CI of difference, -11 to 6.29; P = .60). There was a statistically significant decrease in the percentage of eosinophils in sputum on day 7 of treatment with IVL745 (mean [SEM], 7.32 [1.46]) compared with placebo (mean [SEM], 15.00 [1.92]; 95% CI of difference, -13 to -1.2; P = .02). There was no statistically significant difference between IVL745 and placebo with respect to the early asthmatic response, methacholine hyperresponsiveness, exhaled NO, postallergen sputum, symptoms, inhaled beta2-agonist use, or PEF.


CONCLUSIONS
In patients with mild-to-moderate atopic asthma, IVL745 did not affect the early and late response to inhaled allergen or markers of airway inflammation, except for a modest reduction in sputum eosinophils.
Norris
Virginia
V
Hammersmith Medicines Research, Central Middlesex Hospital, London, United Kingdom. vnorris@hmrlondon.com
Choong
Lee
L
Tran
Duyen
D
Corden
Zoe
Z
Boyce
Malcolm
M
Arshad
Hasan
H
Holgate
Stephen
S
O'Connor
Brian
B
Millet
Sylvaine
S
Miller
Barry
B
Rohatagi
Shashank
S
Kirkesseli
Stephane
S
D000328:Adult; D000485:Allergens / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001555:Benzene Derivatives; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds; D011422:Propionates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012449:Safety
C487626:3-(N-(3,4-dimethoxybenzyl)-2-(2-(3-methoxy-4-(3-o-tolylureido)phenyl)acetylamino)acetamido)propanoic acid; D000485:Allergens; D001555:Benzene Derivatives; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; D011422:Propionates