ETH47 is a novel mRNA drug candidate for the prevention of asthma exacerbations

<bold>Introduction:</bold> Virus infections are the main trigger of asthma exacerbations. Interferon (INF) λ, critical for anti-viral innate immunity, is dysregulated in asthmatics. ETH47 is a novel, nasally delivered mRNA therapeutic encoding INFλ. <bold>Objective:</bold> To investigate safety, tolerability, biodistribution and target engagement of single nasal doses of ETH47 in humans. <bold>Methods:</bold> 40 healthy participants were randomized 3:1 to receive ETH47 or placebo across 5 dose levels (7.2, 36, 175, 700, 1400 µg). Safety endpoints included adverse events (AEs), vital signs, physical examinations, ECGs, and safety laboratory measurements, including cytokines. Serum concentrations of mRNA, LNP and INFλ were measured to determine bioavailability. Target engagement was assessed by measuring INFλ levels in nasal lining fluid (NLF) and expression of interferon-stimulated genes (ISGs) in nasal brush samples. <bold>Results:</bold> Nasal ETH47 was well tolerated. Most AEs were mild, resolved without treatment and were not considered drug-related. There were no changes from baseline or placebo in any of the safety-related endpoints. There was no relevant systemic bioavailability of INFλ, mRNA, or LNP. INFλ concentrations in NLF increased with dose at doses of 36 µg and higher and ranged between 261 and 4,542 pg/mL at 6 hours after dosing. Consistent with increased INF levels in NLF, ISG expression in nasal brushes increased dose-dependently and up to 11-fold across relevant target genes. <bold>Conclusions:</bold> Nasal administration of ETH47 was safe, well tolerated and demonstrated dose-dependent target engagement in humans. Trial results support further clinical development of ETH47 as a novel preventer of asthma exacerbations.