A Phase 3, Randomized, Double-Blinded, Double-Dummy Study Evaluating the Efficacy and Safety of Intravenous Empasiprubart Versus Intravenous Immunoglobulin in Adults With Chronic Inflammatory Demyelinating Polyneuropathy

The primary objective of this study is to demonstrate the efficacy of empasiprubart administered intravenously compared with intravenous immunoglobulin (IVIg) in improving functional ability in participants with chronic inflammatory demyelinating polyneuropathy (CIDP). This objective addresses a key therapeutic need in CIDP, where functional impairment significantly impacts patient independence and daily activities.

The secondary objectives evaluate multiple dimensions of treatment efficacy and safety:

• To demonstrate the efficacy of empasiprubart IV compared with IVIg on activity and social limitations

• To demonstrate the efficacy of empasiprubart IV compared with IVIg on muscle strength and function

• To demonstrate the effect of empasiprubart IV compared with IVIg on time to improvement

• To demonstrate the efficacy of empasiprubart IV compared with IVIg on gait impairment

• To assess the long-term efficacy of empasiprubart IV on gait impairment

• To assess the efficacy of empasiprubart IV compared with IVIg on time to clinical deterioration

• To assess the efficacy of empasiprubart IV compared with IVIg and long-term efficacy of empasiprubart on muscle strength and function

• To assess the efficacy of empasiprubart IV compared with IVIg and long-term efficacy of empasiprubart IV on functional ability

• To assess the long-term efficacy of empasiprubart IV on activity and social limitations

• To assess the effect of empasiprubart IV compared with IVIg and long-term effect of empasiprubart IV on health-related quality of life and patient-reported outcome measures

• To assess the effect of empasiprubart IV on health-related productivity and work productivity

• To assess the immunogenicity of empasiprubart IV in participants with CIDP

• To assess the safety and tolerability of empasiprubart IV compared with IVIg and long-term safety and tolerability of empasiprubart IV in participants with CIDP

• To assess the pharmacodynamic effect of empasiprubart IV in participants with CIDP

• To assess the pharmacokinetics of empasiprubart IV in participants with CIDP

The clinical trial enrolled a total of **110 participants** diagnosed with **chronic inflammatory demyelinating polyneuropathy (CIDP)**. The study population included both **male** and **female** subjects comprising **adults** and **elderly** individuals. Participants were selected based on meeting the diagnostic criteria for CIDP according to EAN/PNS Task Force CIDP guidelines, second revision (2021), and could present with either typical CIDP or specific variants including motor CIDP, **multifocal CIDP** (also known as **Lewis-Sumner syndrome**), **focal CIDP**, or **distal CIDP**. Key selection criteria required that participants had previously responded to **intravenous immunoglobulin (IVIg)** therapy within the past 5 years and were currently receiving IVIg treatment within a standard optimal maintenance dosing regimen, with a minimum weekly dose of at least 0.125 g/kg. Additionally, enrolled subjects demonstrated residual disability and active disease at the time of enrollment. The trial population consisted of **patients** with established disease requiring ongoing treatment.

This is a **Phase 3**, **randomized**, **double-blinded**, **double-dummy** clinical trial evaluating the efficacy and safety of intravenous **empasiprubart** compared with intravenous **immunoglobulin** in adult participants with **chronic inflammatory demyelinating polyneuropathy**. The study utilizes a controlled design with four investigational medicinal products: ARGX-117 (empasiprubart) administered as a **concentrate for solution for infusion**, placebo for empasiprubart, **human normal immunoglobulin** for intravenous use, and placebo for immunoglobulin. All products are administered via **intravenous use**. The active substance empasiprubart is a recombinant monoclonal antibody of protein origin, while human normal immunoglobulin is a blood-derived structurally diverse substance.

The primary objective of the trial is to demonstrate the efficacy of empasiprubart compared with intravenous immunoglobulin in improving functional ability in participants with chronic inflammatory demyelinating polyneuropathy. The **primary endpoint** is defined as a decrease of at least 1 point compared with baseline in **adjusted Inflammatory Neuropathy Cause and Treatment score** at week 24. Secondary endpoints include changes from baseline in the **Inflammatory Rasch-built Overall Disability Scale** centile points score, **Medical Research Council Sum Score**, grip strength in the dominant hand, and **Timed Up and Go** assessment at week 24. Additional secondary endpoints assess time to reduction or increase in adjusted Inflammatory Neuropathy Cause and Treatment score, changes in various functional and quality of life measures over time, work-related activities, incidence and prevalence of **antidrug antibodies** and **neutralizing antibodies**, safety parameters including **adverse events** and laboratory changes, pharmacodynamic markers including free and total **complement component 2**, and serum concentrations of empasiprubart over time.

Participants eligible for enrollment must meet criteria for chronic inflammatory demyelinating polyneuropathy based on European Academy of Neurology/Peripheral Nerve Society Task Force guidelines, second revision (2021). Eligible participants must have either typical chronic inflammatory demyelinating polyneuropathy or one of the following variants: motor chronic inflammatory demyelinating polyneuropathy, multifocal chronic inflammatory demyelinating polyneuropathy (also known as Lewis-Sumner syndrome), focal chronic inflammatory demyelinating polyneuropathy, or distal chronic inflammatory demyelinating polyneuropathy. Additional inclusion criteria require that participants have responded to intravenous immunoglobulin in the past 5 years, are currently receiving treatment with intravenous immunoglobulin within a standard optimal maintenance dosing regimen with a minimum weekly dose of at least 0.125 g/kg, and have residual disability and active disease.

The maximum treatment period for empasiprubart is **120 days**, while the maximum treatment period for human normal immunoglobulin is **24 days**. The estimated recruitment start date is December 4, 2025, with an estimated study completion date of May 31, 2030. The overall trial duration from recruitment initiation to study completion is approximately 4.5 years. Participant involvement includes multiple study visits throughout the treatment and follow-up periods, with assessments conducted at baseline and at specified time points including week 24, which serves as the primary analysis timepoint. Functional assessments, quality of life questionnaires, grip strength measurements, pharmacodynamic sampling, and safety evaluations are performed at designated visits according to the study schedule. Conditions that may lead to early termination from the study may include development of adverse events, withdrawal of consent, protocol violations, or investigator decision based on participant safety considerations.

The experimental medication **ARGX-117** contains the active substance **empasiprubart**, a recombinant humanised **monoclonal antibody** targeting complement component 2. The product is supplied as a **concentrate for solution for infusion** and is administered via **intravenous use**. Empasiprubart is classified as a protein-based therapeutic substance. The maximum treatment period for this investigational medicinal product is 120 days. The sponsor product code for this formulation is ARGX-117 IV.

**Placebo for empasiprubart** is provided as a solution for intravenous infusion. This placebo is designed to match the appearance and administration characteristics of the active empasiprubart formulation to maintain blinding in this double-blinded, double-dummy study design. The placebo does not contain any active pharmaceutical ingredient.

The comparator treatment consists of **human normal immunoglobulin for intravenous use** (**IVIg**), which is a blood-derived structurally diverse substance. The product is supplied as a **solution for infusion** and is administered via **intravenous use**. The maximum treatment period for IVIg in this study is 24 days. The investigational medicinal product and placebo are supplied in original commercial secondary carton packaging boxes, packed and labelled in accordance with Clinical Trials Regulation (Regulation 536/2014 - Annex VI) and applicable country-specific requirements in the official local language.

**Placebo for IVIg** is provided as a solution for intravenous infusion to maintain the double-dummy design of the study. This placebo matches the administration characteristics of the active IVIg comparator and does not contain any active pharmaceutical ingredient. The double-dummy methodology ensures that participants and investigators remain blinded to treatment allocation throughout the study duration.

The primary efficacy endpoint is the decrease of at least 1 point compared with baseline in the adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score at week 24. Secondary efficacy endpoints include change from baseline in Inflammatory Rasch-built Overall Disability Scale (I-RODS) centile points score at week 24, change from baseline in Medical Research Council Sum Score (MRC-SS) at week 24, and change from baseline in grip strength (3-day moving average) in the dominant hand at week 24. Additional secondary endpoints assess time to reduction of at least 1 point from baseline in aINCAT score, change from baseline in Timed Up and Go (TUG) at week 24, and time to increase of at least 1 point compared with baseline in aINCAT score by week 24.

Further secondary endpoints evaluate change from baseline in grip strength (3-day moving average) of both hands over time and change from baseline in grip strength (daily average) for both hands, change from baseline in aINCAT over time, change from baseline in I-RODS centile points score over time, change from baseline in MRC-SS over time, and change from baseline in TUG over time. Patient-reported outcomes include change from baseline in EQ-5D-5L, RT-FSS, SF-12, and BPI-SF over time, as well as Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) values over time. Work-related and household chore activities are assessed using the HRPQ, and the percentage of scheduled hours lost in total (absenteeism plus presenteeism) is measured. Biomarker assessments include absolute values and percentage change from baseline in free C2 and total C2 over time, as well as serum concentrations of empasiprubart over time.