AIR-645

Antisense oligonucleotides (ASOs) bind and facilitate degradation of RNA and inhibit protein expression in pathways not easily targeted with small molecules or antibodies. Interleukin (IL)-4 and IL-13 potentiate signaling through the shared IL-4 receptor-α (IL-4Rα) subunit of their receptors. ASO targeting of IL-4Rα mRNA in a mouse model of asthma led to attenuation of airway hyperactivity, demonstrating potential benefit in asthma patients. This study focused on tolerability of inhaled IL-4Rα-targeting ASOs. Toxicity studies were performed with mouse- (ISIS 23189) and human-specific (ISIS 369645) sequences administered by inhalation. Four week (monkey) or 13 week (mouse) repeat doses at levels of up to 15 mg/kg/exposure (exp) and 50 mg/kg/exp, respectively, demonstrated dose-dependent effects limited to increases in macrophage size and number in lung and tracheobronchial lymph nodes. The changes were largely non-specific, reflecting adaptive responses that occur during active exposure and deposition of ASO and other material in the lung. Reversibility was observed at a rate consistent with the kinetics of tissue clearance of ASO. Systemic bioavailability was minimal, and no systemic toxicity was observed at exposure levels appreciably above pharmacological doses and doses proposed for clinical trials.

The International Quality & Productivity Center's (IQPC) Second Asthma & COPD conference, held in Philadelphia, included topics covering new therapeutic developments in the field of asthma and COPD. This conference report highlights selected presentations on mAb treatments for asthma, including targeting IL-5, IL-13, IL-9 and TNFa, CCR3 inhibitors, histamine H4 receptor inhibition, novel mouse models of COPD and inhaled antisense asthma therapies. Investigational drugs discussed include mepolizumab (GlaxoSmithKline plc), benralizumab (BioWa Inc/Kyowa Hakko Kirin Co Ltd/MedImmune LLC), AMG-317 (Amgen Inc/Takeda Bio Development Center Ltd), TPI-ASM-8 (Pharmaxis Ltd) and AIR-645 (Altair Therapeutics Inc).