Evaluation of VX-522 and Ivacaftor in Adults with Cystic Fibrosis Unresponsive to CFTR Modulator Therapy: A Phase 1/2 Dose-Escalation Study

The primary objective of this Phase 1/2 study is to evaluate the **safety** and **tolerability** of VX-522 in subjects aged 18 years and older with **Cystic Fibrosis** and a CFTR genotype not responsive to CFTR modulator therapy. This is assessed through single ascending doses (SAD) and multiple ascending doses (MAD) of VX-522, including its co-administration with **ivacaftor** (IVA) treatment. The clinical relevance of this objective lies in determining the potential of VX-522 as a therapeutic option for patients with limited treatment alternatives due to their specific CFTR genotype.

Secondary objectives include:

• Evaluating the efficacy of MAD administration of VX-522.
• Assessing the efficacy of multiple doses of VX-522 when co-administered with IVA treatment.

The clinical trial involves a total of **26 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects, aged between 18 and 65 years. Participants are required to have a **body mass index (BMI)** of less than 30.0 kg/m² and a total body weight greater than 50 kg. The trial population was selected based on their stable cystic fibrosis condition, as determined by the investigator, and a forced expiratory volume in one second (FEV1) value of at least 40% of the predicted mean for age, sex, and height. All participants are either nonsmokers or have been ex-smokers for at least three months prior to screening, with their nonsmoking status confirmed by urine or blood cotinine tests. Additionally, participants must be on a stable cystic fibrosis treatment regimen for 28 days prior to dosing and willing to maintain this regimen throughout the study. The trial includes individuals with CFTR mutations on both alleles that are not responsive to CFTR modulator therapy. The study does not provide specific information regarding lifestyle considerations such as diet or physical activity. Participants are required to sign an informed consent form and demonstrate willingness and ability to comply with the study's scheduled visits, treatment plan, and other procedures.

The clinical trial is designed as a **Phase 1/2** study to evaluate the safety, tolerability, and efficacy of **VX-522** in subjects aged 18 years and older with **Cystic Fibrosis** who have a CFTR genotype not responsive to CFTR modulator therapy. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The study is expected to commence on November 1, 2023, and conclude by July 31, 2024, with the total duration of participant involvement varying based on individual response and study arm assignment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body mass index, smoking status, and CFTR mutation responsiveness. Following successful screening, participants will be randomized into treatment arms, with some receiving single ascending doses (SAD) and others receiving multiple ascending doses (MAD) of VX-522, with or without co-administration of **ivacaftor**. The primary endpoint focuses on safety and tolerability, assessed through adverse events, clinical laboratory values, ECGs, vital signs, and immune response. Secondary endpoints include changes in lung function, specifically the percent predicted forced expiratory volume in one second (ppFEV1).

Study visits will include regular follow-up assessments to monitor safety and efficacy, with the end-of-study visit marking the completion of the trial for each participant. The expected length of participant involvement is contingent upon the treatment arm and individual response, with provisions for early termination in cases of significant adverse events or non-compliance with study protocols. Participants are required to adhere to a stable CF treatment regimen throughout the study, excluding the investigational drug. The trial's design ensures rigorous monitoring and data collection to evaluate the investigational product's impact on this specific patient population.

The clinical trial involves the administration of **Kalydeco** 150 mg film-coated tablets, which contain the active substance **ivacaftor**. Ivacaftor is a chemical compound, also known by its synonyms VX-770 and N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The pharmaceutical form of Kalydeco is a film-coated tablet, and it is administered orally. The dosage and frequency of administration are determined based on the study protocol, and the tablets are packaged and labeled specifically for clinical use. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen.

In addition to Kalydeco, the trial also includes the use of VX-522 Nebuliser dispersion, which is an investigational mRNA therapy. The active substance in this formulation is VX-522, a nucleic acid-based compound. VX-522 is administered via inhalation using the eFlow Nebuliser System (Type 678), a CE-marked medical device designed for single-patient use. The nebuliser system is intended for both home use and professional healthcare facility environments and has been modified for optimized delivery of VX-522 in the designated subject group. The dosing schedule for VX-522 is determined by the study protocol, and participant compliance is closely monitored to ensure accurate administration of the investigational product.

The efficacy of the investigational product VX-522 in the clinical trial will be assessed through secondary endpoints, specifically focusing on the change from baseline in percent predicted forced expiratory volume in 1 second (**ppFEV1**). For Treatment Arm 1 (T1), the efficacy will be evaluated by measuring the change in ppFEV1 at Day 29. Similarly, for Treatment Arm 2 (T2), the change from both baseline and pre-Run-in baseline in ppFEV1 at Day 29 will be assessed. These measurements will provide insights into the respiratory function improvements in subjects with **Cystic Fibrosis** who have a CFTR genotype not responsive to CFTR modulator therapy. The assessments will be conducted using spirometry, a standard method for evaluating lung function, ensuring the reliability and validity of the collected data. The schedule for these assessments is aligned with the study's design to capture the necessary data at the specified timepoints, allowing for a comprehensive analysis of the treatment's efficacy.