SPL84 / SpliSense - LARVOL DELTA

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

CF Foundation Provides Up to $8.5M to SpliSense to Support a Clinical Trial for a Potential Treatment for Splicing Mutations (Businesswire) - "The Cystic Fibrosis Foundation is investing up to $8.5 million in additional funds in SpliSense to continue clinical trials for its inhaled antisense oligonucleotide (ASO) drug for people with cystic fibrosis who have certain splicing mutations and potentially other rare mutations. The Foundation's funding will support a planned Phase 2 clinical trial to test the efficacy of SpliSense’s inhaled ASO drug as a potential treatment for the lungs of people with the splicing mutation 3849+10Kb C-to-T. A recent Phase 1a study indicated the drug was safe and well tolerated."

Financing • Cystic Fibrosis

First in Human clinical trial with SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C - > T mutation (NACFC 2023) - "This first-in-human single-dose study was designed to demonstrate safety of a single inhaled dose of SPL84 to support initiation of a Phase 2a multiple ascending dose study in people with CF with the 3849 +10 Kb C- >T mutation. The safety profile of SPL84 in healthy volunteers with normal pulmonary function is promising, with no clinical signs, no significant effect on lung function observed, and low systemic exposure. This demonstration of safety in healthy volunteers supports progression to treatment of people with CF with decreased lung function with the 3849 +10 Kb C- >T mutation with SPL84 in a study planned to be initiated later this year."

Clinical • P1 data

A CFTR super-exon strategy in W1282X intestinal organoids and mice (NACFC 2023) - "(abstract 232): Characterization studies of the chosen device with SPL84... For at least one super exon construct, a human and a mouse super-exon 23–27 can fully restore CFTR function in W1282X mouse intestinal organoids. We have established a line of mice with human super-exon 23–27 and will assess the ability of this to ameliorate CF manifestations."

Preclinical • CFTR

Safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C- >T mutation to support Phase 1/2a clinical study (NACFC 2023) - "These promising preclinical safety results supported initi-ation of a Phase 1/2a clinical study of SPL84. In the Phase 1 study, which was recently successfully completed, safety, tolerability, and pharmacokinetics of a single ascending dose was evaluated in healthy subjects. In the Phase 2a study, which will be initiated later this year, the safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses of SPL84 will be evaluated in people with CF carrying the 3849 mutation."

Clinical • P1/2 data • Cardiovascular • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

SPL84, Antisense oligonucleotide modulating the 3849+10kb C-T splicing defect, efficiently penetrates and restores CFTR function when treated through the apical side of primary HBE cells (NACFC 2023) - "The efficient penetration of SPL84 through the mucus layer from the apical side of the cells into the cell nuclei, leading to rescue of CFTR activity, models the exposure in the person’s lungs to the inhaled drug and highlights the potential of SPL84, currently in a Phase 1/2 clinical study, to provide a significant clinical benefit for people with the 3849 mutation. Antisense oligonucleotide-based drug development for cystic fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation. J Cyst Fibros 2021;20(5):865–75."

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

Nebulizer selection and characterization process with SPL84, an inhaled antisense oligonucleotide, supporting first-in-human clinical study in people with cystic fibrosis with the 3849 mutation (NACFC 2023) - "The data demonstrated that SPL84 remains stable and active when administrated using the chosen nebulizer in various scenarios and therefore can be used in clinical studies for people with CF with the 3849 + 10 kb C-to-T mutation."

Clinical • P1 data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Oncology • Ophthalmology • Pulmonary Disease • Rare Diseases • Respiratory Diseases • USP42

The safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T mutation, supports a phase 1/2 clinical study. (PubMed, Expert Opin Drug Metab Toxicol) - "The NOAEL for mice and monkeys was the highest administered dose in both species, resulting in safety margins ~ 40X the proposed starting clinical dose. These successful results supported initiation of a Phase 1/2 clinical study of SPL84 (ongoing), assessing the safety, tolerability, and pharmacokinetics of a single ascending dose in healthy subjects to be followed by assessment of safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses in CF patients carrying the 3849 mutation."

Journal • P1/2 data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

SpliSense Successfully Completed Phase 1 Study of SPL84, RNA-Based Therapy, for the Treatment of Cystic Fibrosis (PRNewswire) - P1 | N=32 | "Phase 2 efficacy study to be initiated in H1 2024...SpliSense...announced that it has successfully completed a first-in-human, Phase 1 clinical trial of SPL84, the Company's lead inhaled anti sense 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....SPL84 was shown to be safe and well tolerated, and no serious adverse events or significant related adverse events were identified. There were no significant changes from baseline in vital signs, clinical laboratory values, ECG, physical examination, or pulmonary function....In vivo and in vitro studies confirmed the stability of the inhaled drug in CF patient-derived mucus and in lung lysosomal extracts. The mobility of SPL8 through CF Patients hyper-concentrated mucus was also demonstrated."

New P2 trial • P1 data • Preclinical • Trial completion • Cystic Fibrosis • Genetic Disorders

Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. (PubMed, Nucleic Acid Ther) - "Our results, supported by a promising preclinical pharmacological effect of full restoration of cystic fibrosis transmembrane conductance regulator channel activity, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 offers immense opportunities for further development of SpliSense's inhaled ASO-based drugs for unmet needs in pulmonary diseases."

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

Nebulizer selection and characterisation process with SPL84, an inhaled antisense oligonucleotide, supporting first in human clinical study in cystic fibrosis patients carrying the 3849 mutation (ECFS 2023) - "These studies have characterized SPL84 aerosol and demonstrated SPL84 remains stable and active following routine handling use with the nebulizer. In addition, it was also proven SPL84 remains stable following manipulations and holding times occurring in a realistic handling scenario at the clinical site.Based on the data presented, it was demonstrated SPL84 remains stable and active when administrated using the chosen nebulizer in various scenarios, and therefore can be used in upcoming clinical study for CF patients carrying the 3849+10kb C-to-T mutation."

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