SPL84 / SpliSense - LARVOL DELTA

SpliSense Initiates Phase 2b Trial of SPL84 in Cystic Fibrosis (PRNewswire) - "The Phase 2b part 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 randomized, double-blind, placebo-controlled study is expected to enroll approximately 40 pwCF carrying at least one 3849+10kb C→T CFTR 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....Topline results are expected in H2 2027."

P2b data • Trial status • Cystic Fibrosis

SPL84, an inhaled ASO for the treatment of pwCF carrying the 3849 mutation: Comparison of pharmacokinetics between healthy volunteers and pwCF (NACFC 2026) - "SPL84 showed rapid absorption after inhalation in both HVs and pwCF, with generally low systemic exposure and an overall doseproportional PK profile. The low plasma concentrations are expected for an inhaled therapy and are consistent with direct delivery to the target organ and limited systemic exposure, which contributes to SPL84's safety profile by reducing the potential for systemic adverse effects. No accumulation was observed with once-weekly dosing in pwCF, further supporting the favorable safety profile of SPL84."

Clinical • PK/PD data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

SPL84 device characterization supporting dosing in a clinical setting (NACFC 2026) - "Following comprehensive Drug-Device characterization work, it was demonstrated that SPL84 quality and performance attributes were maintained following nebulization process. In parallel, it was also demonstrated that aerosol attributes were in-line with the device manufacturer's published data. Based on the generated characterization data it was made possible for FDA and EMA to clear SPL84 use in combination with the selected device for SpliSense's global clinical program."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

SPL84 integrity is preserved with ETI and inhaled CF therapies, supporting safety of combination use in pwCF with the 3849 + 10kb C→T variant (NACFC 2026) - " SPL84 was incubated in the presence of ETI or inhaled drugs (Dornase alfa (Pulmozyme), Aztreonam (Cayston), Tobramycin (TOBI Podhaler)( at 37°C in 2 different timepoints. This study demonstrated that SPL84 integrity is kept in the presence of ETI and other commonly used CF inhaled drugs. This further support the safety of combined treatment of SPL84 with Trikafta® and other standard of care drugs in clinical setting."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

SPL84 Demonstrates Clinically Meaningful ppFEV1 Improvement in People with Cystic Fibrosis Carrying the 3849 +10 Kb C->T Mutation in Ongoing Phase 2a Study (NACFC 2026) - "This is the first evidence of potential clinical benefit of inhaled ASO therapy in CF, supporting advancement of the program to the expanded 3849 pwCF population. SPL84 had a favorable safety profile and led to a clinically meaningful improvement in lung function in up to ∼70% of participants per cohort. An additional cohort of the Phase 2 study is ongoing, which is evaluating the combined effect of SPL84 and CFTR modulators in 3849 pwCF who are currently treated with modulators."

Clinical • P2a data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

SPL84 Demonstrates Clinically Meaningful ppFEV1 Improvement in People with Cystic Fibrosis Carrying the 3849 +10 Kb C->T Mutation in Ongoing Phase 2a Study (NACFC 2026) - No abstract available

Clinical • P2a data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

SPL84 and trikafta® exhibit comparable and additive effects in patient-derived HBE cells carrying the 3849+10kb C→T/F508del CFTR variants. (PubMed, J Cyst Fibros) - "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®."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

SPL84 demonstrates clinically meaningful ppFEV1 improvement in people with cystic fibrosis carrying the 3849 +10 Kb C->T mutation in a Phase 2a study (ERS 2026) - No abstract available

Clinical • P2a data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2 | N=64 | Recruiting | Sponsor: SpliSense Ltd. | Trial primary completion date: Oct 2025 ➔ Oct 2027 | N=24 ➔ 64 | Trial completion date: Dec 2025 ➔ Dec 2027

Enrollment change • Trial completion date • Trial primary completion date • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Intestinal organoids as a platform for functional evaluation of ASO-mediated splicing modulation in cystic fibrosis. (PubMed, J Cyst Fibros) - "Intestinal organoids, both 3D and monolayers, provide a suitable platform for assessing ASO-based splicing modulation. Our study further implies that the high level of correctly spliced 3849 CFTR transcripts in intestinal epithelial cells may contribute to the mild intestinal symptoms in pwCF carrying non-canonical splicing mutations."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Additive effect of combinational treatment with Splisense ASO Spl84 and Trikafta (NACFC 2025) - " The effect of SPL84, ETI (VX-661, VX-445, VX-770) and the combinational treatment of SPL84+ETI were assessed in HBE cells derived from heterozygous patients carrying the 3849 and F508del mutations. Studies in HBE cells support the potential benefit of combinational treatment with SPL84 and modulator drugs over each drug alone in heterozygote people with CF carrying the 3849 mutation and a modulator responsive mutation. SPL84 is currently in a global phase 2 study assessing both safety and efficacy in people with CF carrying the 3849 mutation."

Comparability assessment of two nebulizers, supporting clinical use expansion of SPL84, an ASO for treatment of pwCF carrying the 3849 m + 10 Kb C- >T mutation (NACFC 2025) - "As demonstrated in table 1 above, the key aerosol performance attributes of both devices were comparable. Therefore, the additional device as assessed by Splisense can further support SPL84 global clinical use expansion through advanced clinical phases for the treatment of pwCF carrying the 3849 mutation."

Clinical

Interim summary of SPL84-002, a Phase 2 study in pwCF carrying the 3849 +10 Kb C- >T mutation evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of SPL84 (NACFC 2025) - "SPL84 has the potential to demonstrate clinical efficacy (e.g., % predicted FEV1 improvement) in pwCF carrying the 3849 mutation. Safety and preliminary efficacy of SPL84 is being evaluated in a global Phase 2 study. Last participant last visit (LPLV) is planned for August 2025; interim results will be available before the conference."

Clinical • P2 data • PK/PD data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Comparison of preclinical and preliminary clinical safety profile of SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C -> T mutation, supporting an ongoing Phase 2 study (ECFS 2025) - "The safety and systemic exposure profile of SPL84 is similar across species (mice, monkeys, and humans). The preclinical and clinical safety profile of SPL84 is promising, with no clinical signs as well as low systemic exposure. This supported the initiation of an ongoing global Phase 2 study for the treatment of 3849 pwCF."

P2 data • Preclinical

Comparability assessment of two nebulizers, supporting clinical use expansion for SPL84, an ASO for treatment of CF patients carrying the 3849+10 Kb C->T mutation (ECFS 2025) - "As demonstrated in Table 1, the key aerosol performance attributes of both devices are considered comparable. Therefore, the additional device assessed by Splisense can further support the SPL84 program through advanced clinical phases for the treatment of pwCF carrying the 3849 mutation."

Clinical

Design of a Phase 2 study in 3849 +10 Kb C->T CF patients to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of SPL84 (ECFS 2025) - "SPL84 has the potential to demonstrate clinical efficacy (e.g., % predicted FEV1 improvement) in pwCF carrying the 3849 mutation. Safety and preliminary efficacy of SPL84 is being evaluated in an ongoing global Phase 2 study. Results of the study will be available in 2025."

Clinical • P2 data • PK/PD data • CFTR

A phase I study assessing the safety and tolerability of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T. (PubMed, J Cyst Fibros) - "SPL84 was safe and well-tolerated when administered as a single inhaled dose to HVs at doses up to 160 mg, with minimal systemic exposure. There were no safety issues observed, no SAEs, no significant related AEs, and, importantly, no significant effect on pulmonary function. The successful completion of the study enabled the initiation of multi-dosing of CF patients in a phase 2 clinical study."

Journal • P1 data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

SPL84 preclinical studies supporting the phase 2 study design (NACFC 2024) - "SPL84 preclinical studies in HBECs support the phase 2 clinical study design initiated in the United States, Europe, Israel and Canada for the treatment of people with CF with the 3849 mutation treated once weekly with inhaled SPL84 in the dose range of 25 to 100 mg."

P2 data • Preclinical

Preclinical and clinical safety profile of SPL84, an antisense oligonucleotide for treatment of people with cystic fibrosis carrying the 3849 +10 Kb C ->T mutation, supporting Phase 2 study initiation (NACFC 2024) - "The safety and systemic exposure profile of SPL84 is similar across species (mice, monkeys, humans). The preclinical and clinical safety profile of SPL84 is promising, with low systemic exposure and no clinical signs. This supported initiation of a global Phase 2 study for the treatment of 3,849 people with CF."

P2 data • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Design of a Phase 2 study in 3849 +10 Kb C->T people with cystic fibrosis to evaluate safety, tolerability, pharmacokinetics, and preliminary efficacy of SPL84 (NACFC 2024) - "SPL84 has the potential to demonstrate clinical efficacy (e.g., ppFEV1 improvement) in PwCF with the 3849 mutation. Safety and preliminary efficacy of SPL84 is being evaluated in an ongoing global Phase 2 study. Results of the study will be available in 2025."

Clinical • P2 data • PK/PD data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

SPL84 efficient and durable effect, restoring 3849 +10kb C-to-T mutated CFTR, when treated through the apical side of primary HBE cells (ECFS 2024) - "Moreover, SPL84 effect was shown to be superior in its effect to TRIKAFTA in 3849 HBE cells. SPL84, was shown to penetrate rapidly through the mucus layer into the epithelial cells. Moreover, SPL84 efficiently penetrated the epithelial cell nuclei, where it needs to act to modulate CFTR splicing. Importantly, as confirmed by the CFFT lab apical treatment of SPL84 in cells from a patient homo and heterozygous for the 3849-mutation led to correction of the splicing defect and to rescue of CFTR activity."

First in Human clinical trial with SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C -> T mutation (ECFS 2024) - "The safety profile of SPL84 in HVs with normal pulmonary function is promising, with no clinical signs and, importantly, no significant effect on lung function observed, as well as low systemic exposure. This demonstration of safety in HVs supports progression to treatment of CF patients with decreased lung function carrying the 3849 +10 Kb C->T mutation with SPL84 in a Phase 2 multiple ascending dose (MAD) study planned to be initiated later this year."

Clinical • P1 data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

SpliSense Receives FDA Fast Track Designation for SPL84 for the Treatment of Cystic Fibrosis (PRNewswire) - "SpliSense...announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to SPL84 for CF. SPL84 is the Company's lead antisense oligonucleotide (ASO) product for the treatment of patients with CF carrying the 3849+10 kilobase (Kb) C->T splicing mutation in the transmembrane conductance regulator (CFTR) gene."

Fast track • Cystic Fibrosis • Genetic Disorders

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Patients With Cystic Fibrosis (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: SpliSense Ltd.

New P2 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

SpliSense Announces FDA Clearance of Investigational New Drug Application for Phase 2 Initiation of SPL84 for the Treatment of Cystic Fibrosis (PRNewswire) - "SpliSense...today announced that the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for the initiation of a Phase 2 study for SPL84 in CF. SPL84 is the Company's lead antisense oligonucleotide (ASO) product for the treatment of people with CF carrying the 3849+10 kilobase (Kb) C->T splicing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene...supported by Phase 1 and preclinical toxicological and pharmacological data demonstrating the potential for full restoration of CFTR protein and activity, based on clinically predictive CF models....The Company has also announced today that it has secured funding from the CF Foundation and other existing investors to support the SPL84 Phase 2 study and additional pulmonary programs."

IND • New P2 trial • Cystic Fibrosis