A Phase 2a, Randomized, Double-blind, Placebo-controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of ALXN1920 in Adult Participants with PMN (Primary Membranous Nephropathy) who are at a High Risk for Disease Progression (AUTUMN)

The primary objective of this study is to evaluate the efficacy of ALXN1920 compared with placebo in participants with primary membranous nephropathy (PMN) who are at high risk for disease progression using 24-hour urine protein-to-creatinine ratio (UPCR). This endpoint is clinically relevant as proteinuria reduction serves as a key indicator of therapeutic response and potential renal outcome improvement in membranous nephropathy.

The secondary objectives include:

• To evaluate the additional efficacy of ALXN1920 compared with placebo in participants with PMN who are at high risk for disease progression

• To evaluate ALXN1920 compared with placebo in participants with PMN who are at high risk for disease progression using biomarkers in urine

• To assess the safety and tolerability of ALXN1920 in participants with PMN who are at high risk for disease progression

• To characterize the pharmacokinetics (PK) of ALXN1920 in participants with PMN who are at high risk for disease progression

• To characterize the pharmacodynamics (PD) of ALXN1920 in participants with PMN who are at high risk for disease progression

• To assess the immunogenicity of ALXN1920 in participants with PMN who are at high risk for disease progression treated with ALXN1920

This clinical trial enrolled a total of **21 participants** diagnosed with **Primary Membranous Nephropathy (PMN)**. The study population consisted of adults aged **18 to 75 years** at the time of informed consent, with both **male and female** participants included. All participants had a documented diagnosis of PMN confirmed by positive **anti-PLA2R antibody** levels exceeding 50 RU/mL as verified by a central laboratory. The trial specifically recruited individuals at **high risk for disease progression**, characterized by significant **proteinuria** with measurements exceeding 3.5 g/day. Participants were required to be receiving **ACE inhibitors or ARBs** for a minimum of 8 weeks prior to screening, with doses titrated to the maximally tolerated level and **systolic blood pressure** controlled below 140 mmHg in at least 75% of readings. As part of the background standard of care and infection risk mitigation, all participants were required to receive prophylactic **antibiotic treatment** while on **rituximab** therapy and to be vaccinated against **Neisseria meningitidis**. The selection criteria ensured enrollment of patients with confirmed membranous nephropathy at substantial risk for disease progression who were adherent to established therapeutic protocols.

This is a **Phase 2a**, **randomized**, **double-blind**, **placebo-controlled**, **parallel-group**, **multicenter** study designed to evaluate the efficacy, safety, tolerability, **pharmacokinetics**, **pharmacodynamics**, and **immunogenicity** of **ALXN1920** in adult participants with **primary membranous nephropathy** who are at high risk for disease progression. The investigational medicinal product ALXN1920 is a solution for injection/infusion administered via **subcutaneous use**, while the control group receives a placebo product. The maximum treatment period is 26 weeks. The study is scheduled to commence participant recruitment in October 2025 with an estimated completion date in March 2027.

The primary objective is to evaluate the efficacy of ALXN1920 compared with placebo using the change from baseline in proteinuria based on 24-hour **urine protein-to-creatinine ratio** as the primary endpoint. Secondary endpoints include additional assessments of proteinuria using both 24-hour and spot urine protein-to-creatinine ratio measurements, changes in **serum albumin**, **anti-PLA2R antibody** levels, peripheral **CD20+ B cell count**, and various urine biomarkers. Safety evaluations encompass the incidence of **treatment-emergent adverse events** and **treatment-emergent serious adverse events**, changes in safety parameters, vital signs, and **electrocardiograms**. Pharmacokinetic assessments involve measuring serum and urine ALXN1920 concentrations over time, while pharmacodynamic evaluations include absolute values and changes from baseline in serum **complement alternative pathway** activity and serum **factor H** levels. Immunogenicity is assessed through **anti-drug antibody** incidence, category of immune response, and titer throughout the study duration.

Eligible participants must be between 18 and 75 years of age at the time of informed consent and have a documented diagnosis of primary membranous nephropathy established by positive anti-PLA2R antibody levels exceeding 50 RU/mL at screening, confirmed by a central laboratory. Participants must be at high risk for disease progression, defined by receiving **angiotensin-converting enzyme inhibitors** or **angiotensin receptor blockers** for a minimum of 8 weeks prior to screening with the dose titrated to the maximally tolerated level. Participants who have not completed 8 weeks of treatment or have not reached the maximally tolerated dose may enter a run-in period for up to 8 weeks. Eligible participants must have **systolic blood pressure** below 140 mmHg in at least 75% of readings within the last 8 weeks and two proteinuria measurements exceeding 3.5 g/day, with the second measurement showing no more than a 50% decrease from the first measurement. All participants must agree to receive background standard of care treatment and prophylactic antibiotic treatment while receiving **rituximab**, as well as vaccination against **Neisseria meningitidis** to reduce the risk of infections.

The study involves a screening visit during which participant eligibility is assessed, including confirmation of diagnosis and evaluation of inclusion criteria. Following successful screening and any necessary run-in period, eligible participants are randomized to receive either ALXN1920 or placebo. The treatment phase extends for a maximum of 26 weeks, during which participants attend scheduled follow-up visits for efficacy assessments, safety monitoring, and collection of pharmacokinetic and pharmacodynamic samples. An end-of-study visit is conducted to perform final evaluations and assessments. Participants may be discontinued from the study early if they meet specific termination criteria, which may include safety concerns, withdrawal of consent, protocol violations, or other conditions as specified in the study protocol. The total duration of participant involvement encompasses the screening period, potential run-in period, 26-week treatment phase, and final study visit.

The experimental treatment consists of **ALXN1920**, also known by the synonym TPP-3621, which is a protein-based investigational medicinal product. ALXN1920 is manufactured by Alexion Pharmaceuticals, Inc. and is supplied as a **solution for injection/infusion**. The active substance is ALXN1920, classified as a protein of other origin. The medicinal product is administered via **subcutaneous use**. The maximum treatment period is **26 weeks**. Specific dosage amounts and frequency of administration are not detailed in the available protocol documentation.

The comparator treatment utilized in this study is **Alxn1920 placebo product**, which serves as the control intervention in this **randomized, double-blind, placebo-controlled** trial design. The placebo product is matched to the experimental treatment to maintain blinding throughout the study. The pharmaceutical form, route of administration, and other specific characteristics of the placebo are designed to be indistinguishable from the active treatment to ensure the integrity of the double-blind methodology. Both the experimental and placebo treatments are administered in parallel groups to adult participants with **primary membranous nephropathy** who are at high risk for disease progression.

Efficacy will be assessed using proteinuria measurements and additional clinical and laboratory parameters. The primary endpoint is the change from baseline in proteinuria based on 24-hour urine protein-to-creatinine ratio (UPCR). Secondary endpoints include change from baseline in proteinuria measured by both 24-hour UPCR and spot UPCR, change from baseline in **serum albumin** levels, change from baseline in anti-PLA2R antibody levels, and change from baseline in peripheral CD20+ B cell count. Additional secondary endpoints encompass change from baseline for urine biomarkers, serum and urine ALXN1920 concentrations over time, and absolute values, change from baseline, and percent change from baseline in serum complement alternative pathway (CAP) activity and serum factor H (fH) levels over time. Safety will be evaluated through the incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) over time, as well as change from baseline in safety parameters, vital signs, and electrocardiograms (ECGs) over time. Immunogenicity will be assessed by measuring anti-drug antibody (ADA) incidence, category of immune response, and titer throughout the duration of the study. The maximum treatment period is 26 weeks.