Bioavailability data of GATA-3-specific DNAzyme demonstrates long-lasting presence in airways of mice, rats, and dogs post inhalation

Marburg, Germany, 15 July 2013

  • No plasma accumulation effects evident in multiple-dose setting

Data published in Toxicology and Applied Pharmacology (Turowska et al., 2013) found that the DNAzyme used in sterna biologicals’ drug candidate SB010, a first-in-class inhaled GATA-3 antagonist for the treatment of moderate to severe Th2-driven asthma, is well-suited for infrequent and convenient dosing approaches.

The researchers investigated the local and systemic distribution of SB010 in naïve mice and mice suffering from experimental asthma as well as pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Intranasal administration of fluorescently labeled SB010 demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled SB010. After intratracheal application, highest amounts of SB010 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic SB010 levels were detected already at 5min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of SB010 were detectable in lungs up to seven days p.a. Also in the toxicologically relevant rats and dogs, SB010 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats.

sterna biologicals is currently evaluating SB010 in a Phase IIa proof-of-concept trial that is expected to complete in H2 2013 (NCT01743768).

Turowska A, Librizzi D, Baumgartl N, Kuhlmann J, Dicke T, Merkel O, Homburg U, Höffken H, Renz H, Garn H. “Biodistribution of the GATA-3-specific DNAzyme hgd40 after Inhalative Exposure in Mice, Rats and Dogs.” Toxicol Appl Pharmacol. 2013 epub ahead of print.

About SB010
sterna biologicals’ drug candidate SB010 is an inhaled DNAzyme-based GATA-3 antagonist. GATA-3 is the master transcription factor in regulating Th2-driven inflammatory diseases such as asthma. It is generally accepted that GATA-3 is necessary and sufficient for the production of key cytokines interleukin (IL)-4, IL- 5, and IL-13, which cause inflammation. In pre-clinical development, SB010 significantly reduced expression of these cytokines and was safe and well-tolerated in toxicological studies with negligible side-effects. DNAzymes are single-stranded DNA molecules comprising a catalytic domain flanked by two binding domains. The binding domains attach to a specific sequence of targeted mRNA (antisense), in case of SB010 GATA-3 mRNA. After binding to the target, the catalytic domain then cleaves the mRNA, thereby inhibiting relevant cytokine expression.

About asthma
Asthma is a major chronic inflammatory disease of the airways affecting an estimated 300 million people worldwide. In OECD countries, prevalence is around 10% and increasing, with greater than average prevalence amongst women, children, and the elderly.