Evaluation of DNTH103 Safety, Tolerability, and Efficacy in Adults with Multifocal Motor Neuropathy: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **safety** and **tolerability** of DNTH103 in participants with **Multifocal Motor Neuropathy** (MMN) up to Week 17. This is clinically relevant as it aims to ensure that DNTH103 can be administered safely to patients, minimizing adverse effects while maintaining patient compliance and comfort.

Secondary objectives include:

• Evaluating the clinical efficacy of DNTH103 on muscle strength and functionality in participants with MMN compared to placebo up to Week 17.
• Assessing the efficacy of DNTH103 on health-related quality of life, fatigue, and treatment satisfaction in participants with MMN compared to placebo up to Week 17.
• Evaluating the safety and tolerability of DNTH103 in participants with MMN over 52 weeks of treatment in the open-label extension (OLE).
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of DNTH103 in participants with MMN.
• Evaluating the immunogenicity of DNTH103.

The clinical trial involves a total of **21 participants** diagnosed with **Multifocal Motor Neuropathy** (MMN). The study population comprises adult males and females aged between **18 to 75 years**, with a weight range of **40 to 120 kg**. Participants were selected based on their confirmed diagnosis of definite or probable MMN and their responsiveness to immunoglobulin (Ig) treatment, while maintaining a stable Ig regimen. Both genders are included, and the trial does not involve a vulnerable population. Participants are required to have documented vaccinations against encapsulated bacteria, adhering to local requirements. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that female participants are of nonchildbearing potential or agree to use effective contraception, while male participants must be surgically sterile or agree to use contraception. The trial aims to evaluate the safety and tolerability of DNTH103 in this specific population over a period of up to 17 weeks.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, pharmacometrics, and efficacy of DNTH103 in adults diagnosed with **Multifocal Motor Neuropathy** (MMN). The trial will involve the administration of DNTH103, a monoclonal antibody, in the form of a solution for injection, either intravenously (IV) or subcutaneously (SC). The study is expected to commence recruitment on January 17, 2025, and conclude by April 30, 2028, with a maximum treatment period of 69 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and a confirmed diagnosis of MMN. The primary objective is to assess the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) up to Week 17. Secondary endpoints include various measures of clinical efficacy, such as time to first retreatment with immunoglobulin (Ig), changes in grip strength, and scores on disability and quality of life scales.

Following the screening, participants will be randomized to receive either DNTH103 or a matching placebo. The trial design ensures that neither the participants nor the investigators will know which treatment is being administered, maintaining the double-blind nature of the study. Regular follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The study will adhere to strict ethical guidelines, ensuring that all participants provide informed consent prior to any study-related activities. The trial aims to provide valuable insights into the potential benefits and risks associated with DNTH103 in the treatment of MMN.

The clinical trial involves the administration of **DNTH103**, an experimental medication developed by Dianthus Therapeutics, Inc. **DNTH103** is a **solution for injection** and is classified as a monoclonal antibody. The pharmaceutical form is specifically designed for administration via **intravenous (IV) or subcutaneous (SC)** routes. The dosing regimen is determined by the study protocol, with a maximum treatment period of 69 days. The medication is not formulated for pediatric use. The active substance, also named **DNTH103**, originates from a protein classified as "Protein - Other." The trial aims to evaluate the safety, tolerability, pharmacometrics, and efficacy of **DNTH103** in adults diagnosed with multifocal motor neuropathy (MMN).

In addition to the experimental treatment, the study includes a **matching placebo** to **DNTH103**. The placebo is utilized to maintain the double-blinded nature of the trial, ensuring unbiased results. The placebo does not contain any active substance and is administered in a manner consistent with the experimental drug to maintain the integrity of the study design. The placebo's pharmaceutical form and route of administration are aligned with those of **DNTH103** to ensure comparability between treatment groups. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of DNTH103 in the treatment of **Multifocal Motor Neuropathy (MMN)** will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs). Secondary endpoints include various measures of clinical efficacy and patient-reported outcomes. These include the time to first retreatment with immunoglobulin (Ig) since the final Ig treatment before randomization, time to first clinical deterioration, and time between first and second retreatment with Ig.

Additional secondary endpoints involve quantitative assessments such as the mean value, mean change, and percentage change from baseline in grip strength, as well as the area under the curve (AUC) of the change from baseline in grip strength. The AUC of the change from baseline in the Medical Research Council (MRC)-10 sum score, mean value and mean change from baseline in MRC-10 and MRC-14 sum scores, and the Multifocal Motor Neuropathy Rasch-Built Overall Disability Scale (MMN-RODS) score will also be evaluated. Functional assessments include the mean value and mean change from baseline in the average time to complete the 9-Hole Peg Test (9-HPT).

Patient-reported outcomes will be measured using the Inflammatory Neuropathy Cause and Treatment (INCAT) Disability score, Euro-Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) scale, and the EQ-5D-5L visual analog scale (VAS). The Patient Global Impression of Change (PGIC) score, Fatigue Severity Scale (FSS) score, and Health-Related Productivity Questionnaire (HRPQ) outcomes will also be assessed. Treatment satisfaction will be evaluated using the Treatment Satisfaction Questionnaire for Medications (TSQM)-14, which includes scores for effectiveness, side effects, convenience, and overall satisfaction.

Biomarker assessments will include serum concentrations of DNTH103 and the incidence and titer of antidrug antibody (ADA) levels against DNTH103. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study, ensuring a comprehensive evaluation of DNTH103's impact on MMN.