Phase 2 Open-Label Study Evaluating Safety, Tolerability, and Efficacy of ARCT-032 (mRNA Encoding Human CFTR Gene) in Cystic Fibrosis Patients

The primary objective of this Phase 2, open-label, multiple ascending-dose study is to evaluate the **safety** and **tolerability** of ARCT-032 in individuals diagnosed with **Cystic Fibrosis**. This is clinically relevant as it aims to ensure that the investigational product, which is a mutation-agnostic mRNA encoding the full-length human CFTR gene, can be safely administered to patients, potentially offering a novel therapeutic approach for managing this genetic disorder.

Secondary objectives include:

• Assessing the **pharmacokinetics** (PK) of ARCT-032 in people with Cystic Fibrosis, which is crucial for understanding the absorption, distribution, metabolism, and excretion of the drug.
• Evaluating the **pharmacodynamic** (PD) activity of ARCT-032, as determined by changes in lung function and quality of life, to determine the drug's effect on the body and its potential impact on patient outcomes.

The clinical trial involves a total of **20 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female adults, aged 18 years and older, who are in a stable pulmonary condition. Participants were selected based on their ability to comprehend and sign an informed consent form, and their willingness to comply with study procedures. Key lifestyle considerations include the requirement for females of child-bearing potential to use effective contraception, and males with partners who are women of child-bearing potential to ensure contraceptive measures are in place. Participants must have a confirmed diagnosis of Cystic Fibrosis, with specific criteria regarding their pulmonary function and eligibility for CFTR modulator therapy. The trial does not involve a vulnerable population, and participants are expected to maintain a stable health status without recent respiratory infections or changes in pulmonary therapy.

The clinical trial is a **Phase 2, open-label, multiple ascending-dose study** designed to evaluate the safety, tolerability, and efficacy of ARCT-032 in individuals diagnosed with **Cystic Fibrosis**. The investigational product, ARCT-032, is a mutation-agnostic mRNA encoding the full-length human CFTR gene, administered via inhalation using the eFlow® Nebulizer System. The trial is expected to commence recruitment on May 1, 2025, and conclude by May 31, 2026. Participants will be involved in the study for a maximum treatment period of one month, with the possibility of early termination if adverse events or other safety concerns arise.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of Cystic Fibrosis, and stable pulmonary status. Participants must be at least 18 years old and meet specific laboratory and clinical parameters. Following the screening, participants will undergo multiple study visits to monitor safety and efficacy outcomes, including adverse events, changes in vital signs, and laboratory test results. The primary endpoints focus on the incidence and severity of adverse events, while secondary endpoints include pharmacokinetics and changes in respiratory symptoms.

The study design does not incorporate blinding or randomization, as it is an open-label trial. Participants will be closely monitored throughout the study duration, with regular assessments to ensure compliance with study procedures and to evaluate the investigational product's impact on lung function and overall health. The end-of-study visit will involve a comprehensive evaluation to assess the long-term safety and efficacy of ARCT-032. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant.

The clinical trial involves the administration of an **experimental medication** known as ARCT-032, developed by Arcturus Therapeutics, Inc. This investigational product is a **mutation-agnostic mRNA encoding the full-length human CFTR gene**. The pharmaceutical form of ARCT-032 is an **inhalation vapour, liquid**, designed for delivery via inhalation. The active substance, mRNA encoding the human CFTR gene, is of nucleic acid origin. The administration of ARCT-032 is facilitated through the eFlow® Nebulizer System, a quiet, lightweight, battery-operated medical device. This device converts the study drug into an aerosol for inhalation, allowing the fine aerosol mist to be inhaled into the lungs. The dosing schedule involves multiple ascending doses, with the maximum treatment period set at one day. The specific dosage and frequency of administration are determined by the study protocol, with compliance monitored throughout the trial.

In addition to the experimental treatment, the study may include the use of a **comparator treatment** or **placebo** as part of the trial design, although specific details regarding these non-experimental treatments are not provided in the available data. The trial aims to evaluate the safety, tolerability, and efficacy of ARCT-032 in individuals with **Cystic Fibrosis**. Participant compliance with the dosing regimen is monitored to ensure adherence to the study protocol, although specific methods of compliance monitoring are not detailed in the provided information.

The efficacy of ARCT-032 in the treatment of **Cystic Fibrosis** will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence, severity, and dose relationship of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs). Additionally, changes from baseline in vital signs, physical examinations, and laboratory test results will be evaluated. The study will also assess bronchospasm by measuring changes from pre-dose to post-dose forced expiratory volume in one second (FEV1).

Secondary endpoints focus on the plasma pharmacokinetics of ARCT-032, specifically the observed concentrations of mRNA in plasma after single and multiple doses. The mean absolute change from baseline in pre-dose percent predicted FEV1 on a specified day of the treatment period will be measured. Furthermore, changes from baseline in the Cystic Fibrosis Questionnaire – Revised Respiratory Symptoms Scale (CFQ-R RSS) score will be assessed on a designated day. These efficacy parameters will be collected and analyzed at predetermined timepoints throughout the study to determine the therapeutic impact of ARCT-032 on patients with Cystic Fibrosis.