Evaluation of Safety, Tolerability, and Efficacy of Inhaled BI 3720931 Gene Therapy in Adults with Cystic Fibrosis Ineligible for CFTR Modulators

The primary objective of this study is to investigate the **safety** and tolerability of a single inhaled dose of BI 3720931 in adult patients with **cystic fibrosis** who are ineligible for CFTR modulators. This is assessed by the number of participants experiencing at least one drug-related, treatment-emergent adverse event (AE) up to Week 24 post-dosing. Additionally, in Phase II, the study aims to demonstrate the superiority of the higher dose of BI 3720931 over placebo (PBO) concerning the primary endpoint, which is the absolute change from baseline in FEV1pp at Week 8. Establishing the safety and efficacy of BI 3720931 is clinically relevant as it may offer a new therapeutic option for patients with cystic fibrosis who cannot benefit from existing CFTR modulators.

Secondary objectives include:

• Phase I: Evaluating clinical efficacy after a single inhaled dose of BI 3720931 based on the number of responders, defined as an absolute change from baseline ≥5% in FEV1pp using the mean of values at Weeks 4, 6, and 8.
• Phase I: Assessing clinical efficacy based on the absolute change from baseline in FEV1pp at Week 24.
• Phase I: Evaluating safety based on the occurrence of dose-limiting toxicities (DLTs) up to Week 24.
• Phase II: Investigating safety and tolerability of BI 3720931 doses based on the occurrence of drug-related adverse events (AEs) and serious adverse events (SAEs) up to Week 24.
• Phase II: Evaluating the efficacy of BI 3720931 doses versus placebo on the absolute change from baseline in FEV1pp at Week 24.

The clinical trial involves a total of **15 participants** diagnosed with **cystic fibrosis**. The study population includes both male and female subjects, specifically those of non-childbearing potential. Participants are selected based on their confirmed diagnosis of cystic fibrosis, characterized by a CF-pulmonary phenotype. The age range of the participants is not specified. All participants must have a stable disease with no pulmonary exacerbation four weeks prior to the screening visit and during the screening period. They must also maintain stable drug and non-drug therapy for cystic fibrosis in the four weeks leading up to dosing. Participants are required to have a forced expiratory volume in one second (FEV1pp) between 50% and 100% of the predicted normal value at Visit 1, based on Global Lung Initiative lung function reference equations. The trial does not include a vulnerable population. Participants may be either naïve to prior gene therapy or have been exposed to prior viral or non-viral gene therapies for cystic fibrosis, provided there are no apparent residual side effects and a sufficient drug-free interval has elapsed since the last dose of prior gene therapy. Further inclusion criteria apply, but specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of a single dose of BI 3720931, an inhaled lentiviral vector gene therapy, in adult individuals with **cystic fibrosis** who are ineligible for CFTR modulators. The trial is structured as a seamless Phase I/II study, beginning with an open-label dose escalation phase followed by a randomized, double-blind, placebo-controlled expansion phase. The estimated duration of the trial extends until February 2027, with recruitment anticipated to start in November 2024.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of cystic fibrosis and the ability to perform spirometric maneuvers. The trial will include follow-up visits to monitor the occurrence of any drug-related, treatment-emergent adverse events (AEs) and to assess changes in lung function, specifically the absolute change from baseline in FEV1pp at Week 8 and Week 24. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 24 weeks post-dosing.

Participants may be withdrawn from the study early if they experience significant adverse events or if they no longer meet the inclusion criteria. The primary endpoints for Phase I include the occurrence of any drug-related, treatment-emergent AEs up to Week 24, while Phase II focuses on the absolute change from baseline in FEV1pp at Week 8. Secondary endpoints include treatment response and the occurrence of serious adverse events (SAEs) up to Week 24. The trial aims to demonstrate the superiority of the higher dose of BI 3720931 over placebo, with a hierarchical testing approach for the lower dose if the primary endpoint is met.

The clinical trial involves the administration of **Gadovist 1.0 mmol/ml solution for injection**, which contains the active substance **gadobutrol**. This pharmaceutical product is a **solution for injection** and is administered via the **intravenous** route. The product is of chemical origin and is manufactured by Bayer PLC. The administration schedule and dosage are determined based on the trial protocol, and participant compliance is monitored throughout the study period.

Another investigational product used in the trial is **BI 3720931**, a **nebuliser solution** containing the active substance of the same name, **BI 3720931**. This product is administered through **inhalation** using a CE-marked nebulizer device. The product is developed by Boehringer Ingelheim International and is classified as a structurally diverse substance. The trial includes a dose escalation phase to determine the optimal dosing regimen, and participant adherence to the inhalation schedule is closely monitored.

The trial also utilizes a **solvent for dilution** specifically for the BI 3720931 inhaler solution. This solvent is used to prepare the nebuliser solution for administration but does not contain an active pharmaceutical ingredient. The solvent's role is auxiliary, facilitating the proper delivery of the BI 3720931 solution during the inhalation process.

Efficacy in this clinical trial will be assessed through a series of predefined endpoints. The primary endpoint for Phase II is the absolute change from baseline in **FEV1pp** (Forced Expiratory Volume in 1 second as a percentage of predicted) at Week 8 following drug administration. This measurement will be used to demonstrate the superiority of the higher dose of BI 3720931 over placebo. If superiority is established, the lower dose will be tested in a hierarchical manner on the same primary endpoint.

Secondary endpoints include the absolute change from baseline in **FEV1pp** at Week 24, and the occurrence of any serious adverse events (SAEs) or drug-related, treatment-emergent adverse events (AEs) up to Week 24 after drug administration. In Phase I, efficacy will also be evaluated by the occurrence of a treatment response, defined as a change from baseline of at least 5% in **FEV1pp**, comparing the mean of three pre-treatment measurements during the screening period with the mean of three post-treatment values at Weeks 4, 6, and 8.

These efficacy parameters will be collected and analyzed at specified timepoints using spirometric maneuvers that adhere to the standards set by the American Thoracic Society/European Respiratory Society. The trial will ensure that all measurements are conducted consistently to maintain the integrity of the data collected.