A Randomized, Double-Blind, Placebo-Controlled Study of Resomelagon in Patients with Idiopathic Membranous Nephropathy and Severe Proteinuria

The primary objective of this study is to evaluate the **safety** of AP1189 compared to placebo in patients with idiopathic membranous nephropathy and severe proteinuria. This will be assessed by monitoring adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms, and laboratory abnormalities. Additionally, the study aims to measure the effect of 12 weeks of treatment on 24-hour urinary protein excretion, expressed as changes from baseline to the end of the treatment period. This is clinically relevant as it provides insights into the potential therapeutic benefits and safety profile of AP1189 in managing proteinuria associated with idiopathic membranous nephropathy.

Secondary objectives include evaluating the results of 12 weeks of treatment on various renal function parameters:

• Changes in 24-hour urinary albumin excretion.
• Changes in plasma albumin levels.
• Number of subjects achieving partial or complete remission at the end of treatment and four weeks post-treatment.
• Changes in estimated glomerular filtration rate (eGFR).
• Changes in 24-hour urinary creatinine clearance (CCr).
• Changes in urinary protein/albumin, plasma albumin, eGFR, and CCr at the four-week post-dosing follow-up visit compared to baseline and end of dosing values.

The clinical trial involves participants diagnosed with **idiopathic membranous nephropathy** and severe proteinuria. The study population includes both male and female subjects aged between 18 to 85 years. Participants are required to have been diagnosed as anti-PLA2-Receptor positive or have a renal biopsy consistent with idiopathic membranous nephropathy within specified timeframes. The trial population was selected based on specific inclusion criteria, including severe proteinuria and an estimated glomerular filtration rate (eGFR) greater than 30 ml/min/1.73m². Participants are required to have been treated with ACE inhibitors or angiotensin II receptor blockers, unless contraindicated. The study includes individuals from Denmark, Norway, and Sweden, with specific criteria for females of childbearing potential. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an **exploratory, randomized, double-blind, multicenter, placebo-controlled** study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of AP1189 in patients with **idiopathic membranous nephropathy** and severe proteinuria. The trial will involve the administration of AP1189 or placebo as an add-on to existing treatment with ACE inhibitors or angiotensin II receptor blockers over a period of 12 weeks. The primary objective is to compare the safety of AP1189 against placebo by assessing adverse events, serious adverse events, vital signs, electrocardiograms, and laboratory abnormalities. Additionally, the trial will measure changes in 24-hour urinary protein excretion from baseline to the end of the treatment period.

Participants will be involved in the study for approximately 12 weeks, with the trial expected to conclude by June 2026. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. Inclusion criteria require participants to be between 18 and 85 years of age, diagnosed with idiopathic membranous nephropathy, and exhibiting severe proteinuria. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study if they experience significant adverse events or if they do not adhere to the study protocol.

The trial will assess both primary and secondary endpoints, including changes in urinary albumin excretion, fractional urine excretion of albumin, plasma albumin levels, and estimated glomerular filtration rate. The study will also evaluate the number of subjects achieving partial or complete remission. The trial is categorized as a Phase 4 therapeutic exploratory and confirmatory clinical trial, indicating its focus on further evaluating the treatment's effects in a larger patient population. The study's design ensures that neither the participants nor the investigators will know which treatment the participants are receiving, maintaining the integrity of the double-blind methodology.

The clinical trial involves the administration of **AP1189 Tablet**, which contains the active substance **resomelagon**. The pharmaceutical form of the experimental medication is a tablet, and it is intended for **oral use**. The dosage is set at a maximum daily dose of 100 mg, with the treatment period extending up to 12 weeks. The administration frequency is once daily. The active substance, resomelagon, is of chemical origin and is provided by Synact Pharma APS. The trial aims to evaluate the safety, tolerability, pharmacokinetics, and efficacy of AP1189 in patients with idiopathic membranous nephropathy and severe proteinuria.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this study. The placebo is identical in appearance to the AP1189 tablet, ensuring the double-blind nature of the trial. The placebo is also administered orally once daily for the same duration of 12 weeks. The use of a placebo allows for the assessment of the true effects of the AP1189 tablet by providing a baseline for comparison. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by evaluating the impact of AP1189 on patients with idiopathic membranous nephropathy and severe proteinuria. The primary efficacy endpoint is the change in 24-hour urinary protein excretion from baseline to the end of the 12-week treatment period. Baseline is defined as the 24-hour urinary protein excretion determined prior to dosing with AP1189 or placebo. Secondary efficacy endpoints include changes in 24-hour urinary albumin excretion, fractional urine excretion of albumin (FEAlb), plasma albumin levels, and estimated glomerular filtration rate (GFR) from baseline to the end of the treatment period. Additionally, the number of subjects achieving partial or complete remission will be evaluated. Complete remission is defined as urinary protein excretion of less than 0.3 g/day with normal plasma albumin and creatinine levels, while partial remission is defined as urinary protein excretion of less than 3.5 g/day with a 50% or greater reduction from peak values, accompanied by improved or normalized plasma albumin and stable plasma creatinine levels. Changes in these parameters will also be assessed at a four-week post-dosing follow-up visit compared to baseline and end-of-treatment values.