A Phase 2b/3 Adaptive, Randomized, Active controlled Study Evaluating the Efficacy, Safety, and Tolerability of Povetacicept Versus Calcineurin Inhibitor in the Treatment of Primary Membranous Nephropathy

The primary objective is to evaluate the efficacy of povetacicept in subjects with primary membranous nephropathy (pMN). This assessment is clinically relevant as it determines whether povetacicept can effectively modify disease outcomes in patients with this glomerular disease characterized by subepithelial immune complex deposition and proteinuria. The secondary objective is to evaluate the safety and tolerability of povetacicept in subjects with pMN, which is essential for establishing the benefit-risk profile of this investigational biologic therapy compared to standard calcineurin inhibitor treatment.

This clinical trial enrolled a total of **91 participants** diagnosed with **primary membranous nephropathy**. The study population included both **male and female subjects** across **adult and elderly age groups**. Participants were selected based on a confirmed diagnosis of primary membranous nephropathy, requiring either a historical biopsy demonstrating the condition or a biopsy performed during the screening period to establish eligibility. The trial population consisted of **patients** with this specific renal disorder. Additional protocol-defined inclusion and exclusion criteria were applied during the selection process, though specific lifestyle considerations such as diet, physical activity, or habits were not disclosed by the sponsor. The study also included a **vulnerable population** as part of its participant cohort.

This is a Phase 2b/3 adaptive, randomized, active-controlled clinical trial evaluating the efficacy, safety, and tolerability of povetacicept compared to calcineurin inhibitor in participants with primary membranous nephropathy. The trial employs an adaptive design with active control, where participants receive either the investigational medicinal product or a comparator treatment. The investigational product povetacicept is administered as a solution for injection or solution for injection in pre-filled syringe via subcutaneous injection, while tacrolimus serves as the active comparator and is administered as hard capsules via oral use. The trial also includes placebo administration to maintain blinding where applicable.

The primary objective is to evaluate the efficacy of povetacicept in subjects with primary membranous nephropathy. The primary endpoint is the proportion of participants achieving Complete Clinical Remission Definition 1 at Week 72. Secondary endpoints include the proportion of participants with Complete Clinical Remission Definition 2 at Week 72, the proportion of participants with Overall Clinical Remission at Week 72, and assessment of safety and tolerability through monitoring of adverse events, clinical laboratory values, standard 12-lead electrocardiograms, and vital signs.

Eligible participants must have a diagnosis of primary membranous nephropathy confirmed by historical biopsy. If no historical biopsy confirming primary membranous nephropathy was previously performed, a biopsy may be conducted during the screening period to establish eligibility. Additional protocol-defined inclusion and exclusion criteria apply to ensure appropriate participant selection.

The maximum treatment period for all investigational products is 72 weeks. The estimated recruitment start date is January 2026, with an estimated study completion date of March 2028. Participant involvement spans the entire treatment period of up to 72 weeks, during which study visits are conducted to assess efficacy parameters, safety monitoring, and collection of clinical data. Screening visits are performed to determine eligibility according to the specified inclusion and exclusion criteria. Follow-up visits occur at regular intervals throughout the treatment period to evaluate treatment response, monitor safety parameters, and collect endpoint data. The end-of-study visit takes place at Week 72 to assess final efficacy and safety outcomes. Participants may be discontinued from the study early based on protocol-defined criteria, including safety concerns, withdrawal of consent, or other conditions specified in the study protocol.

The experimental medication povetacicept (ALPN-303) is administered as a solution for injection in two pharmaceutical forms: solution for injection in pre-filled syringe and solution for injection. The active substance is povetacicept, a protein of non-recombinant origin. The medication is administered via subcutaneous injection. The maximum treatment period is 72 weeks. The dosage is measured in milligrams, though specific dose amounts are not provided in the trial documentation.

Tacrolimus serves as the active comparator treatment in this clinical trial. The medication is provided as a hard capsule for oral use. Tacrolimus is a chemical substance used as a calcineurin inhibitor. The dosage is expressed in milligrams per kilogram body weight. The maximum treatment period for tacrolimus is 72 weeks. Multiple formulations of tacrolimus hard capsules for oral administration are included in the study protocol.

A test investigational medicinal product without active substance is included in the trial. This product serves a specific role in the study design, with a maximum treatment period of 72 weeks. No pharmaceutical form, route of administration, or dosage information is specified for this product.

Efficacy will be assessed using defined clinical remission endpoints in participants with primary membranous nephropathy. The primary efficacy endpoint is the proportion of participants achieving Complete Clinical Remission Definition 1 (CR1) at Week 72. Secondary efficacy endpoints include the proportion of participants achieving Complete Clinical Remission Definition 2 (CR2) at Week 72 and the proportion of participants achieving Overall Clinical Remission (OR) at Week 72. These endpoints will be evaluated to determine the efficacy of povetacicept compared to calcineurin inhibitor treatment over the 72-week treatment period.