Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Povetacicept in Adults with Immunoglobulin A Nephropathy

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the efficacy of **povetacicept** compared with placebo in reducing proteinuria and preserving renal function in adults with Immunoglobulin A Nephropathy (IgAN). This is clinically relevant as proteinuria is a key marker of kidney damage, and preserving renal function is crucial in delaying the progression of IgAN, a condition that can lead to end-stage renal disease.

Secondary objectives include:

• Evaluating the efficacy of povetacicept compared with placebo on slowing kidney failure.
• Assessing the efficacy of povetacicept compared with placebo on improving fatigue.

The clinical trial involves a total of **374 participants** diagnosed with **Immunoglobulin A Nephropathy** (IgAN), confirmed through biopsy. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a 24-hour proteinuria excretion of at least 1.0 gram per day or a 24-hour urine protein-to-creatinine ratio of at least 0.75 gram per gram. Additionally, an estimated glomerular filtration rate of 30 mL/min/1.73m² or higher was required, along with stable use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified. The selection process ensured a representative sample of individuals affected by IgAN, aiming to evaluate the efficacy of povetacicept in reducing proteinuria and preserving renal function compared to a placebo.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **povetacicept** in adults with **Immunoglobulin A Nephropathy** (IgAN). The primary objective is to assess the reduction in proteinuria and the preservation of renal function when compared to a placebo. The trial is expected to span approximately four years, with an estimated recruitment start date in November 2024 and an anticipated end date in August 2028.

Participants will be randomly assigned to receive either povetacicept or a placebo, administered via subcutaneous injection. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress, and a final end-of-study visit. The inclusion criteria require participants to have a biopsy-confirmed diagnosis of IgAN, a 24-hour proteinuria excretion of ≥1.0 g/day or a 24-hour urine protein to creatinine ratio (uPCR) of ≥0.75 g/g, an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m², and stable use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

The primary endpoints include changes from baseline in the 24-hour uPCR at week 36 and the total eGFR slope through week 104. Secondary endpoints involve changes in eGFR at week 104, time to kidney disease progression, and changes in the Functional Assessment of Chronic Illness Therapy-Fatigue Score at week 104. Participant involvement is expected to last up to 104 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is not categorized as low intervention and adheres to the guidelines for a Category 2 trial as per EMA disclosure rules.

The clinical trial involves the administration of **Povetacicept Injection**, an experimental medication developed by Alpine Immune Sciences Inc. Povetacicept is a protein-based therapeutic agent classified under the pharmaceutical form of a **solution for injection**. The medication is administered via **subcutaneous injection**. The trial is designed to evaluate the efficacy of Povetacicept in reducing proteinuria and preserving renal function in adults with Immunoglobulin A Nephropathy. The maximum treatment period for Povetacicept is 104 weeks. The specific dosage and frequency of administration are not detailed in the provided data.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is referred to as "Test IMP without active substance" and does not contain any active pharmaceutical ingredients. The placebo is used as a comparator to assess the efficacy of Povetacicept. The pharmaceutical form, route, and frequency of administration for the placebo are not specified in the available information. The use of a placebo is integral to maintaining the double-blind nature of the study, ensuring unbiased results.

The efficacy of Povetacicept in the treatment of **Immunoglobulin A Nephropathy (IgAN)** will be assessed through a Phase 3, randomized, double-blind, placebo-controlled clinical trial. The primary endpoints for evaluating efficacy include the change from baseline in the 24-hour urine protein to creatinine ratio (uPCR) at Week 36 and the total estimated glomerular filtration rate (eGFR) slope through Week 104. These endpoints will be measured at specified time points, with the uPCR assessed at Week 36 and the eGFR slope evaluated from baseline through Week 104.

Secondary endpoints will further assess efficacy by examining the change from baseline in eGFR at Week 104, the time to kidney disease progression through Week 104, and the change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Score at Week 104. Kidney disease progression is defined as a decline in eGFR of 30% or more, progression to end-stage kidney disease, or death from kidney failure. These parameters will be collected and analyzed at the designated time frames to determine the impact of Povetacicept compared to placebo in preserving renal function and reducing proteinuria in adults with IgAN.