P014 Safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide cystic fibrosis therapeutic

The ASO field is an emerging area of drug development that targets the disease source at RNA level, offering a promising alternative to therapies targeting downstream processes. SpliSense developing SPL84, inhaled for treatment CF patients carrying 3849 +10 kb C->T mutation. In order move into clinic, we performed full battery preclinical safety and toxicology studies with SPL84. vitro in silico specificity off-target showed SPL84 has no effect on non-3849 alleles, homology any human gene sequences, does not influence candidate genes in-vitro partial homology. A vivo pharmacology genotoxicity was completed findings. We also assessed toxicity profile when administered by inhalation, determine NOAEL establish sufficient margins starting clinical dose. weekly via inhalation 4-week Dose Range Finding 9-week GLP mice monkeys. No SPL84-related signs were observed these studies, nor body weight, food consumption, or pathology. All microscopic changes lungs regarded as non-adverse reflected normal clearance process material and/or uptake macrophages airspace local lymph nodes. Systemic exposure both species low, anticipated ASO. monkeys 54.4 20.8 mg/kg/week, respectively, resulting margins. These results supported initiation Phase 1/2a study assess safety, tolerability pharmacokinetics single ascending dose healthy subjects followed assessment tolerability, pharmacokinetics, preliminary efficacy multiple doses