Efficacy of Belumosudil Mesilate and Anhydrous Azithromycin in Chronic Lung Allograft Dysfunction Post-Bilateral Lung Transplantation

The primary objective of this study is to demonstrate the efficacy of **belumosudil** compared with placebo on lung function, specifically measured by forced expiratory volume in 1 second (FEV1), in participants with Stage 1 and 2 chronic lung allograft dysfunction (CLAD) following bilateral lung transplantation. This is clinically relevant as improving FEV1 can indicate better lung function and potentially enhance the quality of life and survival rates in patients experiencing lung transplant rejection.

Secondary objectives include:

• Demonstrating the efficacy of belumosudil compared with placebo on lung function as measured by FEV1 in participants with CLAD following bilateral lung transplantation.
• Evaluating the efficacy of belumosudil on lung function as measured by forced vital capacity (FVC).
• Assessing the effects of belumosudil on CLAD progression.
• Evaluating the efficacy of belumosudil on exercise capacity as measured by the 6-minute walk test.
• Evaluating the effects of belumosudil on patient-reported outcomes (PROs).
• Assessing the safety of belumosudil in participants with CLAD after bilateral lung transplant.

The clinical trial involves a total of **150 participants** who are being studied for **lung transplant rejection**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including being at least one year post bilateral lung transplantation and presenting with Chronic Lung Allograft Dysfunction (CLAD) Stage 1 or 2. The trial includes individuals with a **forced expiratory volume in 1 second (FEV1)** from greater than 50% to 80% of their post-transplant baseline at screening and randomization. Additionally, participants must have received at least eight weeks of azithromycin treatment prior to randomization. The trial population includes a vulnerable population, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel group, Phase 3 study** to evaluate the efficacy of oral **belumosudil** in adult participants with chronic lung allograft dysfunction (CLAD) following bilateral lung transplantation. The trial will be conducted over an estimated duration from October 2023 to March 2029. Participants will be randomly assigned to receive either the investigational product, belumosudil, or a placebo, with the primary objective being to demonstrate the efficacy of belumosudil compared with placebo on lung function, specifically measuring the forced expiratory volume in 1 second (FEV1). The study will include a series of visits, starting with a screening visit to confirm eligibility, followed by regular follow-up visits to monitor progress and collect data, and concluding with an end-of-study visit to assess the overall outcomes.

Participants will be involved in the study for a maximum treatment period of 34 weeks. The inclusion criteria require participants to be at least one year post-bilateral lung transplantation and to present with CLAD Stage 1 or 2, with FEV1 from greater than 50% to 80% of post-transplant baseline at screening and randomization. Additionally, participants must have received at least 8 weeks of azithromycin prior to randomization. The primary endpoint is the percent change from baseline to Week 26 in FEV1, while secondary endpoints include response rate at Week 26, absolute changes in FEV1 and FVC, time to CLAD progression, and various patient-reported outcomes. Conditions that may lead to early termination from the study include significant adverse events or failure to adhere to the study protocol. The trial will also include open-label extensions following the double-blind phase to further assess the long-term effects of the treatment.

The clinical trial involves the administration of **belumosudil mesilate**, marketed under the product name SAR445761, which is provided in the form of a **film-coated tablet**. The active substance, belumosudil mesilate, is of chemical origin and is developed by Sanofi Aventis Recherche et Développement (SAR). The medication is administered orally with a maximum daily dose of 400 mg, and the total dose over the treatment period can reach up to 413,600 mg. The treatment duration is set for a maximum of 34 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the study includes the use of **anhydrous azithromycin** as a comparator treatment. This substance is also of chemical origin and is administered in a pharmaceutical form identified as PHF00170MIG. The route of administration is oral, with a maximum daily dose of 250 mg and a total dose limit of 111,000 mg over the 34-week treatment period. The inclusion of azithromycin serves as a standard-of-care therapy to evaluate the efficacy of the experimental treatment in comparison.

The trial also involves a placebo group, which will receive tablets with the same excipients except for the absence of hypromellose. The placebo is administered orally, mirroring the administration schedule of the experimental treatment to maintain the study's double-blind design. Compliance with the placebo administration will be monitored to ensure the integrity of the trial results.

The efficacy of the investigational product, **belumosudil**, will be assessed in a Phase 3 clinical trial involving adult participants with chronic lung allograft dysfunction (CLAD) following bilateral lung transplantation. The primary endpoint for evaluating efficacy is the percent change from baseline to Week 26 in forced expiratory volume in 1 second (FEV1). Secondary endpoints include the response rate at Week 26, defined as the proportion of participants with a decline of 10% or less in FEV1 compared with baseline, and absolute changes from baseline to Week 26 in FEV1 and percent predicted FEV1. Additional secondary endpoints involve changes in forced vital capacity (FVC), time to CLAD progression, time to re-transplantation or death, changes in 6-minute walk distance, and various patient-reported outcomes.

Measurements of FEV1 and FVC will be conducted at baseline and at Week 26, utilizing standardized pulmonary function tests. The 6-minute walk distance will also be assessed at these timepoints. Patient-reported outcomes will be evaluated using the Saint George Respiratory Questionnaire (SGRQ), EQ-5D-5L, and the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) profile version 2.1. These assessments will provide comprehensive data on the impact of the treatment on lung function, physical capacity, and quality of life. The trial will also monitor the number of participants experiencing adverse events and serious adverse events throughout the double-blind treatment period and the open-label extensions.