Dose–response effects of TPI ASM8 in asthmatics after allergen

• Published in: Allergy (Copenhagen) Vol. 66; no. 9; pp. 1242 - 1248
• Main Authors: Gauvreau, G. M., Pageau, R., Séguin, R., Carballo, D., Gauthier, J., D’Anjou, H., Campbell, H., Watson, R., Mistry, M., Parry‐Billings, M., Killian, K., Renzi, P. M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Blackwell
• Subjects: Adolescent; Adult; allergen challenge; Allergens; Allergens - administration & dosage; Allergens - immunology; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - adverse effects; Anti-Asthmatic Agents - pharmacokinetics; Anti-Asthmatic Agents - therapeutic use; Antisense oligonucleotides; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - immunology; beta subunit of IL‐3, IL‐5, and GM‐CSF receptors; BID protein; Biological and medical sciences; CCR3 receptor; Chemokine receptors; Chronic obstructive pulmonary disease, asthma; Cytokine Receptor Common beta Subunit - genetics; Dermatology; Dose-response effects; Dose-Response Relationship, Drug; Drug dosages; Drug therapy; Eosinophil cationic protein; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Granulocyte-macrophage colony-stimulating factor; Humans; Inflammation; Interleukin 3; Interleukin 5; Leukocytes (eosinophilic); Male; Medical sciences; methacholine; Phosphorothioate Oligonucleotides - administration & dosage; Phosphorothioate Oligonucleotides - adverse effects; Phosphorothioate Oligonucleotides - pharmacokinetics; Phosphorothioate Oligonucleotides - therapeutic use; Pneumology; Receptors, CCR3 - genetics; Respiratory Hypersensitivity - drug therapy; Respiratory Hypersensitivity - immunology; Respiratory tract; RNA, Messenger - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sputum; Sputum - immunology; Young Adult; Allergy; Subunit; Beta; Dose activity relation; Immunology; Interleukin 5; Interleukin 3; Dicotyledones; Angiospermae; Bronchus disease; Obstructive pulmonary disease; beta subunit of IL-3; Biological receptor; Lung disease; Immunopathology; Respiratory disease; Dermatology; Cytokine; IL-5; CCR3 chemokine receptor; Antisense oligonucleotide; allergen challenge; Chenopodiaceae; Asthma; and GM-CSF receptors; CCR3 receptor; antisense oligonucleotides; Spermatophyta; Granulocyte macrophage colony stimulating factor; Allergen; Provocation test
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/j.1398-9995.2011.02638.x

To cite this article: Gauvreau GM, Pageau R, Séguin R, Carballo D, Gauthier J, D’Anjou H, Campbell H, Watson R, Mistry M, Parry‐Billings M, Killian K, Renzi PM. Dose–response effects of TPI ASM8 in asthmatics after allergen. Allergy 2011; 66: 1242–1248. Background:  TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (βc) of the IL‐3, IL‐5, GM‐CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics. Objective:  We assessed whether TPI ASM8 caused a dose‐dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC). Methods:  This single‐center, open‐label, stepwise‐ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I‐Neb™ nebuliser. Treatments were separated by 2–3‐week washout periods. Results:  TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post‐AIC, P = 0.016 and P = 0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P = 0.016) and 59%, (P = 0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P = 0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P = 0.012). A dose–response relationship was noted, and efficacy was maintained with once per day administration. Conclusions:  TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL‐3, and GM‐CSF also are important targets for the management of asthma.