Asthma diagnosis and treatmentEffect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma
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
References (29)
- et al.
Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease
Trends Pharmacol Sci
(2003) - et al.
Very late antigen (VLA-4) antagonists as anti-inflammatory agents
Curr Opin Chem Biol
(1998) - et al.
Anti-inflammatory effects of low-dose oral theophylline in atopic asthma
Lancet
(1994) - et al.
Leukotriene D4 receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma
J Allergy Clin Immunol
(1992) - et al.
Effect of nedocromil sodium on the late asthmatic reaction to bronchial antigen challenge
J Allergy Clin Immunol
(1989) - et al.
Allergen induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber
J Allergy Clin Immunol
(1982) - et al.
Analysis of cellular and biochemical constituents of induced sputum after allergen challenge: a method for studying allergic airway inflammation
J Allergy Clin Immunol
(1994) - et al.
Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response
Lancet
(2000) Verdict in the case of therapies versus eosinophils: the jury is still out
J Allergy Clin Immunol
(2004)- et al.
Asthma
N Engl J Med
(2001)
Adhesion to fibronectin prolongs eosinophil survival
J Exp Med
Adhesion to fibronectin primes eosinophils via α-4, β-1
Immunology
Small molecule antagonists of α4 integrins: novel drugs for asthma
Exp Opin Invest Drugs
Blockade of the late-phase airways responses and airway hyper-responsiveness in allergic sheep with a small-molecule peptide inhibitor of VLA-4
Am J Respir Crit Care Med
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Pharmacological opportunities to control inflammatory diseases through inhibition of the leukocyte recruitment
2016, Pharmacological ResearchCitation Excerpt :Further Phase II studies are being conducting to assess the effects on white blood cell counts in the cerebrospinal fluid [117]. Still, IVL745 and IVL745, small molecule antagonists of α4β1, were previously tested on allergen-induced bronchoconstriction in patients with asthma [118]. However, the clinical trials aimed to treat asthmatic patients failed to demonstrate efficacy greater than that observed with placebo [117].
Integrins: Therapeutic targets in airway hyperresponsiveness and remodelling?
2014, Trends in Pharmacological SciencesCitation Excerpt :Furthermore, a correlation between eosinophil β1 integrin activation and decreased lung function has been observed in a young-adult, non-severe subpopulation of patients with asthma [25]. Despite in vivo animal experiments showing an important role for α4β1 integrins in allergen-induced inflammation [23,26,27], clinical trials investigating small-molecule integrin α4β1 antagonists, such as IVL745, BIO-1211, and HMR 1031, in asthmatic patients showed that these compounds were relatively ineffective, demonstrating only a slight reduction in sputum eosinophils for IVL745, but without effect on AHR [27,28]. In theory, this class of drugs appeared to be promising due to the high affinity (Kd in the picomolar range) and a 200-fold higher selectivity for the activated α4β1 integrin [29].
Cellular Adhesion in Inflammation
2014, Middleton's Allergy: Principles and Practice: Eighth EditionEosinophil Trafficking
2013, Eosinophils in Health and DiseaseEosinophil Trafficking
2012, Eosinophils in Health and DiseaseHarnessing opportunities in non-animal asthma research for a 21st-century science
2011, Drug Discovery TodayCitation Excerpt :Although mice have been useful for mechanistic studies looking at switching off, suppressing or upregulating single molecular pathways [72,75], transgenic mouse studies are only able to illustrate the importance of a particular mediator or pathway in that particular animal using a specific protocol. When expanding many studies to larger interventions, such as knockout molecules and increasing the range of animal models, it is often the case that the results are not transferrable to the human condition, as is the case with Very Late Antigen-4 (VLA-4), bradykinin, IL-4, and neurokinin studies [76–78]. In total, three studies involving mice have identified airway response targets, have translated to human clinical benefits, for each of these targets substantive human evidence was also available [79].
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.