Long-term Safety and Efficacy Evaluation of Inhaled Lentiviral Vector Gene Therapy BI 3720931 in Cystic Fibrosis Patients from Previous Clinical Trial

The primary objective of this clinical trial is to evaluate the **long-term safety** of BI 3720931, an inhaled lentiviral vector gene therapy, in participants with cystic fibrosis who have received at least one dose. This assessment is crucial for determining the sustained safety profile of the therapy, which is essential for its potential use as a long-term treatment option for cystic fibrosis, a chronic and life-limiting condition.

The secondary objective is to investigate the duration of clinical efficacy in trial participants after the initial dosing of BI 3720931 over a period of at least two years. This objective aims to provide insights into the longevity of the therapeutic benefits, which is important for understanding the potential of BI 3720931 to maintain clinical improvements over an extended period.

The clinical trial involves a total of **15 participants** diagnosed with **cystic fibrosis**. The study population includes both male and female subjects, with an age range that encompasses both children and adolescents. Participants were selected based on their prior involvement in a previous BI-sponsored trial with BI 3720931, having received at least one dose of the investigational drug or a matching placebo. The trial does not specifically target a vulnerable population. Participants' general health status is consistent with individuals managing cystic fibrosis, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria ensure that all participants have provided informed consent in accordance with International Council for Harmonisation-Good Clinical Practice and local legislation.

The clinical trial is designed to evaluate the long-term safety and durability of efficacy of **BI 3720931**, an inhaled lentiviral vector gene therapy, in individuals with **cystic fibrosis**. This study is a continuation for participants who have previously received at least one dose of **BI 3720931** or a matching placebo in a prior trial. The trial is structured as a long-term observational study, with a duration extending up to 15 years from enrollment. The primary objective is to monitor the occurrence of treatment-emergent delayed adverse events (AEs), including new malignancies, serious neurologic disorders, rheumatologic or autoimmune disorders, hematologic disorders, and potentially product-related infections.

The trial follows a **randomized, double-blind, controlled** design. Participants will be required to attend several study visits throughout the trial period. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on the principal inclusion criteria, which include prior participation in a BI-sponsored trial with **BI 3720931** and receipt of at least one dose of the investigational product. Informed consent must be obtained in accordance with International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines.

Subsequent follow-up visits will be scheduled to assess the time to loss of efficacy, defined as a drop in forced expiratory volume in 1 second (FEV1) to below 5% above baseline, and to monitor the occurrence of AEs and serious adverse events (SAEs) throughout the study. The presence of replication-competent lentivirus (RCL) will also be evaluated. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 15 years, unless early termination is warranted due to significant safety concerns or withdrawal of consent.

Participants may be withdrawn from the study if they experience severe adverse reactions, if the investigational product is deemed unsafe, or if they choose to withdraw consent. The trial is not classified as low intervention and is conducted to gather comprehensive data on the long-term effects of the therapy in a controlled environment. The study is expected to commence recruitment on May 19, 2025, with an estimated end date of October 1, 2046.

The clinical trial involves the administration of **BI 3720931**, an experimental medication formulated as a **nebuliser solution**. This investigational product is designed for **inhalation** and is administered using a CE-marked nebulizer device. The active substance, **BI 3720931**, is classified as a structurally diverse substance. The trial aims to evaluate the long-term safety and efficacy of this inhaled lentiviral vector gene therapy in individuals with cystic fibrosis who have previously participated in a related clinical trial. The administration involves a single dose, and the primary objective is to assess the long-term safety in participants who have received at least one dose of BI 3720931.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the investigational product, BI 3720931. The trial does not specify a maximum daily dose, total dose, or treatment period, indicating that the administration is limited to a single dose. Participant compliance is monitored through the use of the nebulizer device, ensuring accurate delivery of the medication. The nebulizer, a CE-marked device, is integral to the administration process, facilitating the inhalation route required for the delivery of the nebuliser solution.

The efficacy of the clinical trial involving **cystic fibrosis** patients treated with BI 3720931 will be assessed through several key endpoints. The primary endpoint focuses on the occurrence of treatment-emergent delayed adverse events (AEs), such as new malignancies, serious neurologic disorders, rheumatologic or autoimmune disorders, hematologic disorders, or potentially product-related infections, monitored up to 15 years from enrolment. Secondary endpoints include the time to loss of efficacy, defined as a drop to below 5% above baseline in forced expiratory volume in 1 second, percent of predicted value (FEV1pp), and the time to first pulmonary exacerbation (PEX) from dosing. Additionally, the occurrence of adverse events (AEs) will be tracked up to 2 years after enrolment, while serious adverse events (SAEs) and replication-competent lentivirus (RCL) will be monitored throughout the study duration, which extends up to 15 years.