Phase 3 Randomized Double-Blind Study of Empasiprubart vs. Human Normal Immunoglobulin (IV) in Adults with Multifocal Motor Neuropathy

The primary objective of this study is to demonstrate the efficacy of **empasiprubart** compared to intravenous immunoglobulin (IVIg) in improving muscle strength in adults with **Multifocal Motor Neuropathy**. This is clinically relevant as muscle strength is a critical factor in the management and quality of life for patients with this condition.

Secondary objectives include:

• Part A - To demonstrate the efficacy of empasiprubart compared to IVIg on functional ability, motor function, and manual dexterity.
• Part A - To evaluate the safety and tolerability of empasiprubart compared to IVIg.
• Part A - To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of empasiprubart.
• Part A - To evaluate the efficacy of empasiprubart compared to IVIg on muscle strength, motor function, manual dexterity, and patient-reported outcomes.
• Part A - To evaluate the effect on health-related quality of life for empasiprubart compared to IVIg.
• Part B - To evaluate the long-term efficacy of empasiprubart in improving functional ability, muscle strength, motor function, manual dexterity, quality of life, and patient-reported outcomes.
• Part B - To evaluate the long-term safety and tolerability of empasiprubart.
• Part B - To evaluate the PK, PD, and immunogenicity of empasiprubart.
• Part B - To evaluate the effect of empasiprubart on long-term health-related quality of life.

The clinical trial involves a total of **68 participants** diagnosed with **Multifocal Motor Neuropathy** (MMN). The study population includes both male and female subjects, aged 18 years and older, who have a confirmed diagnosis of definite or probable MMN according to the EFNS/PNS 2010 guidelines. Participants have previously responded to intravenous immunoglobulin (IVIg) treatment within the past five years and are currently on a maintenance regimen of IVIg. The trial population was selected based on their ongoing IVIg treatment, with specific dosing intervals and requirements. Participants are required to have documented immunization against encapsulated bacterial pathogens or be willing to receive immunization prior to the study. The study does not include vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of **empasiprubart** compared to **intravenous immunoglobulin (IVIg)** in adults diagnosed with **Multifocal Motor Neuropathy**. The trial is structured in a **double-dummy** format to ensure blinding and involves the administration of both the investigational product and a placebo. The study is expected to span a total duration of approximately 49 weeks, with participant involvement lasting up to 49 weeks, depending on individual treatment response and adherence to protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous response to IVIg. Following successful screening, participants will be randomized to receive either empasiprubart or IVIg, with follow-up visits scheduled at regular intervals to monitor efficacy and safety outcomes. These visits will include assessments of muscle strength, laboratory tests, and evaluations of any adverse events. The primary endpoint is the change from baseline in grip strength in the most affected hand at week 24. Secondary endpoints include changes in various clinical scores and the incidence of adverse events.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the comparative effectiveness of empasiprubart and IVIg, contributing valuable insights into the management of Multifocal Motor Neuropathy.

The clinical trial involves the administration of **HUMAN NORMAL IMMUNOGLOBULIN (IV)**, a solution for infusion, as an experimental treatment. This medication is derived from a structurally diverse blood-derived substance and is intended for intravenous infusion. The product is supplied in vials within original commercial secondary carton packaging, labeled according to CTR (Regulation 536/2014 - Annex VI) and country-specific requirements. The maximum treatment period for this medication is 39 weeks. The administration schedule and dosage are determined by the clinical trial protocol, with compliance monitored throughout the study.

Another experimental treatment in the trial is **ARGX-117**, also known as empasiprubart, which is a recombinant monoclonal antibody. This product is provided as a concentrate for solution for infusion and is administered via intravenous infusion. The active substance, empasiprubart, is a protein of other origin, specifically an anti-complement 2 IgG humanized monoclonal antibody. The maximum treatment period for ARGX-117 is 49 weeks. The dosing is expressed in milligrams per kilogram (mg/kg), and the administration schedule is outlined in the study protocol, with participant compliance being closely monitored.

The study also includes a **placebo solution for IV infusion** as a comparator treatment. The placebo is designed to mimic the experimental treatments in appearance and administration route, ensuring the study remains double-blinded. The placebo is administered via intravenous infusion, and its use is critical for maintaining the integrity of the study's blinding process. The placebo is supplied in a manner consistent with the experimental treatments, ensuring consistency in packaging and labeling.

The efficacy of the investigational product, **empasiprubart**, will be assessed in a Phase 3, randomized, double-blinded, double-dummy clinical trial comparing its effects to those of intravenous immunoglobulin (IVIg) in adults with **Multifocal Motor Neuropathy** (MMN). The primary endpoint for evaluating efficacy is the change from baseline in grip strength (GS) in the most affected hand at week 24. Secondary endpoints include changes from baseline in the MMN-RODS centile score, mMRC-14 sum score, and CAP-PRI total score at week 24, as well as the percentage change from baseline in the time to complete the 9-Hole Peg Test (9-HPT) with the dominant hand at week 24.

Additional secondary endpoints involve patient-reported outcomes such as the PGI-C actual value over time, and clinically meaningful changes in laboratory parameters, vital signs, and ECG results. The incidence and severity of adverse events (AEs) and adverse events of special interest (AESIs), as well as the incidence of serious adverse events (SAEs), will also be monitored. Pharmacokinetic parameters of empasiprubart, including serum concentrations over time, will be evaluated. The presence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against empasiprubart in serum will be assessed to determine immunogenicity.

Measurements will be collected at specified time points, including baseline and week 24, using validated scales and laboratory tests. The trial will employ tools such as the MMN-RODS, mMRC-14, and CAP-PRI scales, as well as the 9-HPT, to ensure accurate and reliable assessment of efficacy parameters. Data analysis will focus on changes from baseline, percentage changes, and actual values over time to comprehensively evaluate the efficacy of empasiprubart in improving muscle strength and other relevant clinical outcomes in patients with MMN.