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.

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Journal
European Respiratory Journal
Published
2026-10-15
DOI
https://doi.org/10.1183/13993003.00866-2026
Primary Topic
Cystic Fibrosis Research Advances
Type
article
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article

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

Virginija Kalinauskaitė-Žukauskė, Renske van der Meer, Stefano Costa, Kęstutis Malakauskas et al.
European Respiratory Journal
Cystic Fibrosis Research Advances
article

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

Virginija Kalinauskaitė-Žukauskė, Renske van der Meer, Stefano Costa, Kęstutis Malakauskas, Eitan Kerem, Antonio Álvarez Fernández, Karen McCoy, Lital Friedman, Andrea Gramegna, C. Schwarz, Pavel Dřevı́nek, Szczepan Cofta, Henryk Mazurek, Gili Hart, Almudena Felipe Montiel, Efrat Ozeri-Galai, Daria Springer, Eva Berešová, Batsehva Kerem, Asaf Cohen, Stanley Fiel, Rebecca Cagnina
article en

Abstract

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.

European Respiratory Journal
Poznan University of Medical Sciences (PL), Hebron University (PS), Boston Children's Hospital (US), Nationwide Children's Hospital (US), Lithuanian University of Health Sciences (LT), Hebrew University of Jerusalem (IL), Charles University (CZ), Hadassah Medical Center (IL), Instituto de Salud Carlos III (ES), Morristown Medical Center (US), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Ospedale Maggiore (IT), University Hospital in Motol (CZ), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Vall d'Hebron Institut de Recerca (ES), Vall d'Hebron Hospital Universitari (ES), Instytut Gruźlicy i Chorób Płuc (PL), Centrum Onkologii (PL), Azienda Ospedaliera Universitaria Policlinico "G. Martino" (IT), Haga Hospital (NL), Boston Children's Museum (US), Slovak Environmental Agency (SK), Fakultní nemocnice Motol a Homolka (CZ)
Good health and well-being
Openalex Percentile: Top 13%
Cystic Fibrosis Research Advances
DOISourceOpenAlex
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