Evaluation of NNC0519-0130 Versus Semaglutide and Placebo in Chronic Kidney Disease with or without Type 2 Diabetes and Obesity: A Dose-Response Study

The primary objective of this study is to **demonstrate** and characterize the dose-response relationship of once weekly subcutaneous administration of NNC0519-0130 in terms of relative reduction in the urinary albumin-to-creatinine ratio (UACR). This is clinically relevant as UACR is a key marker for assessing kidney function and progression of **chronic kidney disease** (CKD), which can lead to significant morbidity and mortality if not managed effectively.

Secondary objectives include comparing the effect of once weekly subcutaneous NNC0519-0130 versus placebo on:

• Surrogate markers of CKD progression
• Weight-related parameters
• Glycaemic control
• Blood pressure
• Safety and tolerability

The clinical trial involves a total of **366 participants** diagnosed with **Chronic Kidney Disease**, with or without **Type 2 diabetes** and **Obesity**. The study population includes both **female** participants of non-childbearing potential and **male** participants, all aged **18 years or above**. Participants were selected based on specific health criteria, including a **Body Mass Index (BMI)** of **27.0 kg/m²** or higher and kidney impairment defined by serum creatinine and cystatin C-based eGFR between **15 and 90 mL/min/1.73 m²**. Additionally, albuminuria is defined by a urinary albumin-to-creatinine ratio (UACR) between **100 and 5000 mg/g**. Participants are required to be on a stable dose of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) unless contraindicated or not tolerated. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy**, safety, and pharmacokinetics of NNC0519-0130 administered once weekly via subcutaneous injection, compared to semaglutide 1.0 mg and a placebo, in individuals with **chronic kidney disease** (CKD), with or without type 2 diabetes, and with overweight or obesity. This is a randomized, double-blind, controlled trial with a primary objective to demonstrate and characterize the dose-response relationship of NNC0519-0130 concerning the relative reduction in urinary albumin-to-creatinine ratio (UACR). The trial is expected to last until September 2026, with participant recruitment starting in December 2024. The total duration of participant involvement is anticipated to be up to 36 weeks, with the possibility of early termination if specific safety concerns arise or if the participant withdraws consent.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of type 2 diabetes, body mass index (BMI), and kidney function. Following successful screening, participants will be randomized to receive either NNC0519-0130, semaglutide, or placebo. The study includes multiple follow-up visits at weeks 12, 24, and 36 to monitor changes in UACR, estimated glomerular filtration rate (eGFR), body weight, waist circumference, glycated hemoglobin (HbA1c), and blood pressure. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints, including the number of treatment-emergent adverse events (TEAEs).

Inclusion criteria require participants to be adults aged 18 years or older, with a BMI of at least 27.0 kg/m², and diagnosed with CKD as defined by specific serum creatinine and cystatin C-based eGFR levels. Participants must also have albuminuria and be on a stable dose of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless contraindicated. The trial excludes individuals who do not meet these criteria or who have conditions that may interfere with the study outcomes. The trial's design ensures rigorous assessment of the investigational product's impact on CKD progression and associated metabolic parameters.

The clinical trial involves the administration of **NNC0519-0130**, a solution for injection, which is synthetically produced and contains the active substance NNC0519-0130. This investigational medication is administered subcutaneously once weekly. The pharmaceutical form is a solution for injection, and the maximum treatment period is 36 weeks. The dosing schedule is designed to evaluate the dose-response relationship concerning the reduction in urinary albumin-to-creatinine ratio in participants with chronic kidney disease, with or without type 2 diabetes, and with overweight or obesity. Participant compliance will be monitored throughout the study to ensure adherence to the dosing regimen.

**Ozempic 0.5 mg**, containing the active substance **semaglutide**, is used as a comparator in this study. It is provided as a solution for injection in a pre-filled pen, specifically the PDS290 pen-injector, which is a disposable, pre-filled, multi-dose device capable of delivering the required doses subcutaneously. The clinical variant of the pen-injector is assembled in smaller batch sizes than the marketed product. The administration frequency is once weekly, and the maximum treatment period is 36 weeks. The study will monitor participant compliance to ensure accurate dosing and administration.

**Placebo A** is utilized as a control in the trial. It does not contain any active substance and is used to assess the efficacy and safety of the investigational medication and comparator. The placebo is administered in a manner consistent with the other treatments in the study, ensuring blinding and maintaining the integrity of the trial design. Compliance with placebo administration will be monitored to ensure consistency across all study arms.

The efficacy of the investigational product NNC0519-0130 will be assessed in a clinical trial involving participants with chronic kidney disease, with or without type 2 diabetes, and with overweight or obesity. The primary endpoint for evaluating efficacy is the change in the urinary albumin-to-creatinine ratio (UACR) from baseline (week 0) to the end of a given maintenance dose period (week 12, 24, or 36). This endpoint is designed to demonstrate and characterize the dose-response relationship of once-weekly subcutaneous administration of NNC0519-0130.

Secondary endpoints include changes in estimated glomerular filtration rate (eGFR) based on creatinine and cystatin C (CKD-EPI 2021) from baseline to the end of treatment, relative change in body weight, achievement of ≥5% and ≥10% weight reduction, change in waist circumference, change in glycated hemoglobin (HbA1c) from baseline to the end of a given maintenance dose period, and changes in systolic and diastolic blood pressure from baseline to the end of treatment. Additionally, the number of treatment-emergent adverse events (TEAEs) will be recorded from baseline to the end of the study.