Asthma diagnosis and treatment
Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma

https://doi.org/10.1016/j.jaci.2005.04.045Get rights and content

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 β2-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 β2-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 β2-agonist use, or PEF.

Conclusion

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.

Section snippets

Methods

The study was done at 3 centers (Southampton General Hospital, Hampshire; Kings Hospital, London; and HMR, Central Middlesex Hospital, London). The study was approved by each center's local research ethics committee, and all subjects gave fully informed, written consent. The study was performed in accordance with the International Conference of Harmonization Guideline for Good Clinical Practice.

Safety and tolerability

Safety and tolerability were very good. Adverse events were similar in nature and incidence with IVL745 and placebo. Thirty-one all-causality adverse events were reported during the study. Sixteen (all mild) were reported with placebo, and 15 (14 mild and 1 moderate [muscular skeletal shoulder pain]) were reported with IVL745. The most common adverse events were headache (6 with placebo and 6 with IVL745), nasopharyngitis (2 with IVL745 and 1 with placebo), diarrhea (1 with placebo and 1 with

Discussion

The effect of IVL745, a VLA-4 antagonist, on the early and late response to inhaled allergen and markers of airway inflammation in patients with mild-to-moderate atopic asthma was assessed in this study. The dose administered was 20 mg twice daily via the Ultrahaler metered-dose dry-powder inhaler. This was considered the maximum feasible dose given the number of actuations required for dosing by using the formulation (10 actuations for 20 mg). There was no effect of IVL745 on the LAR, which

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    Supported by Aventis Pharmaceuticals.

    Disclosure of potential conflict of interest: B. O'Connor had had ad hoc consultancy arrangements with GlaxoSmithKline, AstraZeneca, Altana, Aventis, Celgene, Pfizer, Boehringer Ingelheim, and various small biotechnology companies and receives grant and research support from several pharmaceutical companies. As director of a phase 2 clinical research unit, he performs a number of studies similar to that reported in this article; Kings College receives the funding. He has spoken for AstraZeneca, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Altana. B. Miller and S. Kirkesseli possess shares of stock and stock options in and are employees of Sanofi-Aventis (formerly Aventis). S. Rohatagi was an employee of Aventis at the time of this study.

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