SpliSense Initiates Phase 2b Trial of Inhaled ASO SPL84 as Add-On to CFTR Modulators in Cystic Fibrosis
核心洞察
SpliSense (搜索) has launched a Phase 2b trial of SPL84, an inhaled antisense oligonucleotide for cystic fibrosis (搜索) patients carrying the 3849+10kb C→T CFTR (搜索) splicing mutation.
The randomized, double-blind, placebo-controlled study will enroll about 40 patients on stable Trikafta/Kaftrio or Alyftrek therapy, randomizing them 4:1 to 50 mg SPL84 or placebo.
The primary objective is safety and tolerability over 12 weeks of once-weekly inhalation, with efficacy assessments including ppFEV1, ppFEF25-75 and CFQ-R respiratory domain.
SpliSense (搜索), a clinical-stage biotechnology company developing RNA-based therapies for pulmonary diseases, announced the initiation of the Phase 2b clinical trial of SPL84, its lead inhaled antisense oligonucleotide (ASO) therapy, for the treatment of people with cystic fibrosis (搜索) (pwCF) carrying the 3849+10kb C→T splicing mutation in the CFTR (搜索) gene. The Phase 2b portion of the ongoing SPL84-002 study is designed to demonstrate the clinical impact of SPL84 when added to stable standard-of-care CFTR modulator therapy.
The announcement, dated Sept. 16, 2026, from Jerusalem, follows the earlier Phase 2a part of SPL84-002, in which the company reported a favorable safety profile and encouraging clinical activity. Improvement in lung function, defined as a change from baseline in ppFEV1 of at least 5 points, was observed in up to 70% of SPL84-treated participants. Building on those findings, the Phase 2b study will further define the safety profile and substantiate the treatment effect of SPL84 in the current modulator-treatment setting.
Trial Design and Endpoints
The randomized, double-blind, placebo-controlled study is expected to enroll approximately 40 pwCF carrying at least one 3849+10kb C→T CFTR (搜索) allele who are receiving stable Trikafta®/Kaftrio® or Alyftrek™ therapy. Participants will be randomized approximately 4:1 to receive 50 mg of SPL84 or matched placebo by inhalation once weekly for 12 weeks.
The primary objective of the study is to evaluate safety and tolerability. Efficacy assessments include pulmonary function, including ppFEV1 and ppFEF25–75, and respiratory symptoms measured by the CFQ-R respiratory domain. Exploratory assessments include sputum microbiology and Lung Clearance Index. Topline results are expected in H2 2027. Additional information is available at ClinicalTrials.gov under NCT06429176.
"Following the favorable safety and efficacy profile demonstrated in the Phase 2a study, we are excited to initiate the Phase 2b study, designed to determine whether once-weekly SPL84 can provide additional clinical benefit for people with the 3849+10kb C→T mutation who are already receiving standard-of-care CFTR (搜索) modulator therapy," said Gili Hart, Ph.D., Chief Executive Officer of SpliSense (搜索). "We selected the 50 mg dose based on the favorable Phase 2a safety profile and the consistent encouraging clinical activity observed at this dose. Given SPL84's RNA-level mechanism, which is distinct from CFTR modulators, we believe there is a strong scientific rationale for evaluating the combination."
Mechanism and Preclinical Rationale
SPL84 is a once-weekly inhaled ASO designed to correct the RNA splicing defect caused by the 3849+10kb C→T mutation. By binding selectively to mutant CFTR (搜索) pre-mRNA, SPL84 redirects splicing toward correctly formed CFTR transcripts, with the goal of increasing production of functional CFTR protein.
In preclinical studies, SPL84 fully restored CFTR (搜索) activity in gold-standard pharmacological models. Additional published preclinical studies also showed an additive increase in CFTR functional activity when SPL84 was combined with Trikafta®/Kaftrio®, providing additional support for evaluating the combination clinically.
SPL84's RNA-level mechanism is distinct from CFTR (搜索) modulators, which act at the protein level. Although CFTR modulators are approved for pwCF carrying the 3849+10kb C→T mutation, clinical responses have been reported to be moderate and variable, supporting the rationale for evaluating SPL84 as an add-on therapy.
Regulatory Designations and Pipeline
SPL84 has received Fast Track and Orphan Drug designations from the U.S. Food and Drug Administration (搜索) and PRIME designation from the European Medicines Agency (搜索).
SpliSense (搜索)'s proprietary platform is designed to modulate RNA processing and gene expression directly in the lung, enabling both mutation-specific correction and selective modulation of disease-driving proteins. The company is advancing a pipeline that includes SPL84 and SPL23 for cystic fibrosis (搜索), SPL5AC targeting MUC5AC (搜索) for muco-obstructive lung diseases including COPD (搜索), NCFB and asthma (搜索), and SPL5B targeting MUC5B (搜索) for IPF (搜索). Clinical data from the Phase 2a study of SPL84 provide proof-of-concept for SpliSense's inhaled ASO platform and support the broader application of its lung-directed RNA approach across the pipeline.
"More broadly, SPL84 provides important clinical experience supporting our inhaled ASO approach for pulmonary diseases," Hart added. "We look forward to the Phase 2b topline results, expected in the second half of next year."