Multiple Dose ASM8 in Mild Asthmatics

• Evaluation of the safety and tolerability of ASM8.
• Comparison of the allergen-induced early asthmatic response (EAR) between ASM8 and placebo.
• Comparison of the allergen-induced airway hyperresponsiveness between ASM8 and placebo.
• Comparison of the allergen-induced changes in sputum eosinophils at 7 and 24 hours post allergen, between the ASM8 and placebo.
• Determination of the plasma and sputum pharmacokinetic profile of single- and repeated-doses of ASM8 in patients with mild asthma.
• Determination of the pharmacodynamic activity of ASM8 on specific gene expression, protein levels, differential cell counts, and eosinophilic cationic protein (ECP), as measured in sputum samples.
• Relief medication use in the ASM8 versus placebo

• • Evaluation of the safety and tolerability of ASM8.
• • Comparison of the allergen-induced early asthmatic response (EAR) between ASM8 and placebo.
• • Comparison of the allergen-induced airway hyperresponsiveness between ASM8 and placebo.
• • Comparison of the allergen-induced changes in sputum eosinophils at 7 and 24 hours post allergen, between the ASM8 and placebo.
• • Determination of the plasma and sputum pharmacokinetic profile of single- and repeated-doses of ASM8 in patients with mild asthma.
• • Determination of the pharmacodynamic activity of ASM8 on specific gene expression, protein levels, differential cell counts, and eosinophilic cationic protein (ECP), as measured in sputum samples.
• • Relief medication use in the ASM8 versus placebo

To determine the safety and efficacy of multiple doses of ASM8 antisense oligonucleotides in asthmatics.

This is a double-blind, placebo-controlled, crossover trial to evaluate the safety, tolerability and efficacy of inhaled ASM8 for the treatment of allergen-induced asthma. Individuals with stable, mild to moderate allergic asthma by American Thoracic Society (ATS) criteria (1), with a history of episodic wheeze and shortness of breath, will be eligible for enrolment. The study is divided into 2 parts.

Inclusion Criteria:

• Part 1: Men and women 18 to 65 years of age; generally good health; mild to moderate, stable, allergic asthma as defined by ATS criteria (1); history of episodic wheeze and shortness of breath; forced expiratory volume in 1 second (FEV1) at baseline ≥70% of the predicted value; able to comprehend and follow all required study procedures; willing and able to sign an informed consent form.

Part 2: Methacholine challenge at baseline (PC20 ≤16 mg/mL); positive skin-prick test to common aeroallergens (cat, dust mite, grass, pollen) and positive allergen-induced early and late airway bronchoconstriction.

Exclusion Criteria:

• Part 1 and Part 2: Significant acute or chronic medical or psychiatric illness; known coagulopathy, worsening of asthma or respiratory infection in the preceding 6 weeks; use of inhaled or oral corticosteroids within the last 28 days, antihistamines, immunosuppressives, nonsteroidal anti-inflammatory drugs, or anticoagulants (intermittent doses of short-acting β2-agonist are allowed); use of medications that may interact with ASM8; investigational drug use within 30 days; any clinically significant abnormality on screening laboratory determinations; current tobacco use in previous 3 months or 10 pack-years; pregnant or lactating women; women actively seeking pregnancy or who are not using adequate contraception; history of serious adverse effect (SAE) or hypersensitivity to any drug; 20% decrease in FEV1 or FVC with baseline saline in methacholine challenge during screening.