Evaluation of Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Cystic Fibrosis Patients with 3849+10 Kb C->T Mutation

The primary objective of this study is to evaluate the **safety** and **tolerability** of multiple ascending doses of SPL84 administered by inhalation in participants with cystic fibrosis (CF). This is clinically relevant as it aims to identify the maximum tolerated dose (MTD), which is crucial for determining the safe dosage range for further clinical development. Understanding the safety profile of SPL84 is essential for ensuring patient safety and guiding future therapeutic strategies for CF, a genetic disorder that significantly impacts respiratory function.

Secondary objectives include:

• Characterizing the pharmacokinetics (PK) and excretion of multiple ascending doses of SPL84 administered by inhalation in participants with CF. This will provide insights into the drug's absorption, distribution, metabolism, and excretion, which are vital for optimizing dosing regimens.
• Assessing the preliminary efficacy of multiple ascending doses of SPL84 administered by inhalation in participants with CF. This will help determine the potential therapeutic benefits of SPL84, contributing to the understanding of its clinical utility in managing CF symptoms.

The clinical trial involves a total of **6 participants** diagnosed with **cystic fibrosis**. The study population includes both male and female adults aged 18 and above, with a body mass index (BMI) of at least 17 kg/m². Participants are required to have two cystic fibrosis-causing mutations, specifically the 3849+10 Kb C->T mutation on one allele in the CFTR gene, confirmed by a certified genetic laboratory. The trial population was selected based on stable lung function, with FEV1 values between 40-90% predicted at screening, and no more than 20% lower than the highest absolute FEV1 within 120 days prior to the start of the trial. Participants must be non-smokers or non-vapers for at least 180 days prior to screening. The trial includes a vulnerable population, as defined by the study criteria.

The clinical trial is a **Phase 2a**, randomized, placebo-controlled, double-blind study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of SPL84 in patients with **cystic fibrosis** carrying the 3849 +10 Kb C->T mutation. The trial involves the administration of multiple ascending doses of SPL84 via inhalation using a nebulizer. The study aims to identify the maximum tolerated dose (MTD) in participants. The trial is expected to commence recruitment on September 16, 2024, and conclude by April 3, 2025.

Participants will be randomly assigned to receive either the investigational product, SPL84, or a placebo solution for inhalation. The study is double-blind, meaning neither the participants nor the investigators will know which treatment the participants are receiving. The trial will include several study visits, beginning with a screening visit to assess eligibility based on criteria such as age, diagnosis, and lung function. Eligible participants are adults aged 18 and above with a confirmed diagnosis of cystic fibrosis and specific genetic mutations.

The trial will consist of multiple visits over a period of up to nine weeks, during which participants will undergo various assessments. These include monitoring for adverse events, changes in vital signs, clinical laboratory values, electrocardiograms, and pulmonary function tests. The primary endpoints focus on the incidence and severity of adverse events, while secondary endpoints include pharmacokinetic parameters, spirometry results, and changes in body weight and antibiotic treatment.

Participants are expected to be involved in the study for the entire duration unless specific conditions necessitate early termination. Such conditions may include the occurrence of serious adverse events or significant deviations from the inclusion criteria. The study will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall safety and efficacy of the investigational product.

The clinical trial involves the administration of an **experimental medication** known as SPL84, which is a **synthetic nucleic acid**. The active substance is a complex nucleic acid sequence, specifically 2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiocytidylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiouridylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioguanylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiocytidylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiocytidylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioguanylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiouridylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioguanylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioguanylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioguanylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-P-Thioadenylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-P-Thiocytidylyl-(3'-O->5'-O)-2'-O-(2-Methoxyethyl)-5-Methyl-Uridine Sodium Salt. The pharmaceutical form of SPL84 is a **solution for nebulization**, and it is administered via **inhalation** using the Aerogen InnoSpire Go nebulizer. The maximum daily dose is 100 mg, with a total treatment period of up to 9 days. The nebulizer employs vibrating mesh technology to ensure consistent delivery of aerosol with an optimal particle size suitable for deep lung deposition.

The trial also includes a **placebo solution for inhalation** as a comparator treatment. The placebo is designed to mimic the experimental medication in appearance and administration method but does not contain the active substance. The placebo is administered in the same manner as SPL84, using the same nebulization device, to maintain blinding and ensure the integrity of the study results. The placebo serves as a control to evaluate the safety, tolerability, and preliminary efficacy of SPL84 in patients with **cystic fibrosis** carrying the 3849 +10 Kb C->T mutation.

The efficacy of the investigational product SPL84 in patients with **Cystic Fibrosis** will be assessed through several secondary endpoints. These include the characterization of pharmacokinetic (PK) parameters based on the concentration of SPL84 in plasma and urine. Spirometry will be utilized to measure pulmonary function, specifically focusing on forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced mid-expiratory flow (FEF25-75). Additionally, the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS) will be employed to evaluate respiratory symptoms. Changes in body weight and antibiotic treatment will also be monitored as part of the efficacy assessment.