Efficacy and Safety Evaluation of DNTH103 in Adults with Chronic Inflammatory Demyelinating Polyneuropathy: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to demonstrate the **efficacy** of DNTH103 compared to placebo based on the time to relapse in adults with **Chronic Inflammatory Demyelinating Polyneuropathy** (CIDP). This is clinically relevant as it aims to establish the potential of DNTH103 in prolonging the time to relapse, which is a critical factor in managing CIDP and improving patient outcomes.

Secondary objectives include:

• Demonstrating the efficacy of DNTH103 compared to placebo based on the proportion of relapsing participants during Part B.
• Evaluating the efficacy based on changes in the Inflammatory Rasch-built Overall Disability Scale (I-RODS) disability scores during Part B.
• Assessing changes in grip strength in the dominant hand during Part B.
• Evaluating efficacy in Part A and Part B based on measures of muscle strength and disability.
• Assessing efficacy based on health-related quality of life outcomes.
• Evaluating the long-term efficacy and durability of response during the open-label extension (OLE).
• Assessing the safety and tolerability of DNTH103.
• Evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of DNTH103.
• Assessing the immunogenicity of DNTH103.

The clinical trial involves a total of **324 participants** diagnosed with **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)**. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, indicating a broad adult demographic. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of CIDP, a **CIDP Disease Activity Status (CDAS)** score of 3 or higher, and neurological stability. The trial population is characterized by a weight range between 40 kg and 120 kg. Lifestyle considerations such as current or past treatment with immunoglobulin or corticosteroids, as well as vaccination status against encapsulated bacteria, are relevant to the study. The trial includes a vulnerable population, ensuring comprehensive representation of the CIDP patient demographic. Participants must have provided written informed consent and adhere to contraceptive guidelines if applicable. The selection process ensures a diverse and representative sample of individuals affected by CIDP, facilitating the evaluation of the efficacy of DNTH103 compared to placebo.

The clinical trial is a **Phase 3 randomized, double-blind, placebo-controlled study** designed to evaluate the efficacy and safety of DNTH103 in adults with **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)**. The primary objective is to demonstrate the efficacy of DNTH103 compared to placebo based on the time to relapse. The trial is expected to commence recruitment on September 1, 2025, and conclude by December 31, 2030. Participants will be randomly assigned to receive either DNTH103, a monoclonal antibody solution for injection, or a placebo matching DNTH103. The maximum treatment period is 172 days, with a maximum daily dose of 1200 mg and a total dose not exceeding 50100 mg.

The study will include several key visits: an initial **screening visit** to confirm eligibility based on inclusion criteria such as a confirmed diagnosis of CIDP, a CIDP Disease Activity Status (CDAS) score of ≥ 3, and neurological stability. Participants must also meet specific treatment history requirements. Following the screening, participants will undergo regular **follow-up visits** to monitor their response to treatment and assess any adverse events. The **end-of-study visit** will evaluate the overall outcomes and safety of the treatment. The primary endpoint is the time from the first dose to relapse, assessed by the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) score. Secondary endpoints include changes in grip strength, I-RODS score, and the incidence of treatment-emergent adverse events.

Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial is structured to ensure rigorous assessment of the investigational product's efficacy and safety, adhering to high standards of clinical research methodology.

The clinical trial involves the administration of **DNTH103**, an experimental medication developed by Dianthus Therapeutics, Inc. **DNTH103** is a **monoclonal antibody** formulated as a **solution for injection**. The active substance, also named **DNTH103**, is derived from a protein of other origin. The medication is administered via injection, with a maximum daily dose of 1200 mg and a total maximum dose of 50100 mg over the course of the treatment period, which spans up to 172 days. The primary objective of the trial is to evaluate the efficacy of **DNTH103** in adults with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) by assessing the time to relapse.

The study also includes a **placebo** group, which receives a placebo matching **DNTH103**. The placebo is designed to mimic the experimental medication in appearance and administration method, ensuring the study remains double-blind. The placebo does not contain any active substance and serves as a comparator to evaluate the true efficacy of **DNTH103**. Participants' compliance with the dosing schedule is monitored throughout the trial to ensure accurate and reliable results.

The efficacy of DNTH103 in the treatment of **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time from the first dose to relapse, as evaluated by the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) score. Secondary endpoints include the proportion of participants who relapse, changes in the Inflammatory Rasch-built Overall Disability Scale (I-RODS) score, grip strength in both the dominant and nondominant hands, and the Medical Research Council Sum Score (MRC-SS). Additional assessments will include changes in the Euro-Quality of Life Visual Analogue Scale (EQ-VAS) and the Fatigue Severity Scale (FSS).

These efficacy parameters will be measured at various timepoints throughout the trial, including Parts A, B, and the Open-Label Extension (OLE) phase. The trial will also monitor the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), serum concentrations of DNTH103, and the incidence and titer of antidrug antibodies (ADAs). The assessments will utilize validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.