SPL84 and trikafta® exhibit comparable and additive effects in patient-derived HBE cells carrying the 3849+10kb...

The 3849+10kb C→T (3849) splicing variant in the CFTR gene creates a cryptic exon containing a stop codon, reducing wild-type mRNA and producing non-functional protein. Although Trikafta® (ETI) is approved for people with cystic fibrosis (pwCF) carrying this variant, clinical responses are often modest and variable, underscoring the need for therapies that directly target the 3849 splicing defect. SPL84 is an inhaled antisense oligonucleotide (ASO) designed to restore normal splicing. In a Phase 2a study, SPL84 demonstrated encouraging clinical benefit signals and a favorable safety profile. Here, we evaluated the therapeutic potential of combining SPL84 with ETI and assessed whether this combination provides additional benefit compared with either treatment alone in pwCF carrying the 3849 variant and a Trikafta-responsive variant on the second allele.

Primary human bronchial epithelial (HBE) cells from five donors heterozygous for the 3849 and F508del variants were treated with SPL84 and/or ETI. CFTR function was assessed using Ussing chamber and TECC-24. Splicing modulation was confirmed by RT-PCR and RT-qPCR.

SPL84 and ETI alone produced comparable restoration of CFTR function. Importantly, combining SPL84 with ETI resulted in a significant additive effect, increasing CFTR activity by an average of 86% over ETI alone across donors.

These findings provide proof-of-concept that combining SPL84 with ETI achieves superior CFTR functional restoration. This approach of simultaneously rescuing the F508del protein and restoring WT CFTR production from the 3849 allele, will be further evaluated in a Phase 2b combination study of SPL84 and Trikafta®.