A phase 2a study with SPL84: A novel RNA-targeted approach to restore CFTR function in people with CF carrying the 3849+10 kb C→T mutation

Background The 3849+10 kb C→T mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leads to aberrant splicing and the inclusion of a cryptic exon harboring a premature stop codon, resulting in the production of non-functional CFTR protein. SPL84 is an inhaled antisense oligonucleotide (ASO) designed to correct CFTR splicing and restore functional CFTR expression in people with CF (pwCF) carrying this mutation. Methods This Phase 2a randomized, placebo-controlled, double-blind, multiple ascending dose study evaluated safety, tolerability, pharmacokinetics, and exploratory efficacy of inhaled SPL84 in pwCF carrying the 3849+10 kb C→T mutation. Participants received once-weekly inhalations of SPL84 (25 or 50 mg) or placebo for 9 weeks. Exploratory efficacy measures included changes in ppFEV1, ppFEF25–75, and CFQ-R respiratory symptom score. Results Seventeen participants were included in the analysis, with fifteen completing all treatments. SPL84 was well tolerated with no drug-related serious adverse events. Most adverse events were mild or moderate and consistent with the underlying CF disease. Improvements in lung function, defined as change from baseline in ppFEV1≥5, were observed in up to 70% of the treated participants per cohort, accompanied by improvement of additional efficacy outcomes. Conclusions Inhaled SPL84 demonstrated a favorable safety profile together with encouraging signals of clinical benefit in pwCF carrying the 3849+10 kb C→T mutation. These findings represent, to our knowledge, the first evidence of potential clinical benefit from a nucleic acid–based therapy targeting RNA in a pulmonary disease, supporting further evaluation of SPL84 as a mutation-specific, RNA-targeted treatment.