Efficacy and Safety Evaluation of Riliprubart in Refractory Chronic Inflammatory Demyelinating Polyneuropathy: A Phase 3 Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of riliprubart relative to placebo in participants with refractory chronic inflammatory demyelinating polyneuropathy (CIDP). This is assessed using the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The clinical relevance of this objective lies in determining the potential of riliprubart to improve functional outcomes in patients who do not respond to standard treatments, thereby addressing a significant unmet medical need in this patient population.

Secondary objectives include:

• Evaluating the efficacy of riliprubart relative to placebo as assessed by additional measures of disability and impairment.
• Assessing the long-term efficacy of riliprubart with additional measures of disability and impairment.
• Evaluating the efficacy of riliprubart in immunoglobulin-refractory participants as measured by the INCAT disability scale.
• Assessing the effect of riliprubart relative to placebo on quality of life and fatigue, including long-term effects.
• Evaluating the safety, tolerability, and immunogenicity of riliprubart, including long-term assessments.
• Assessing the delayed efficacy of riliprubart.

The clinical trial involves a total of **118 participants** diagnosed with **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)**. The study population includes both male and female subjects, with an age range that encompasses both adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of CIDP or its variants, and a history of refractoriness to either immunoglobulin or corticosteroid therapy. The trial population is characterized by a diverse health status, with individuals having active disease as indicated by a CIDP disease activity score of 2 or more. Lifestyle considerations such as diet and physical activity are not specified, but participants are required to maintain stable doses of any allowed immunosuppressant drugs or low-dose oral corticosteroids prior to screening. The study also includes a vulnerable population, ensuring comprehensive representation. Key inclusion criteria necessitate the use of contraception methods during and after the study, adherence to local regulations regarding contraception, and documented vaccinations against encapsulated bacterial pathogens within the specified timeframe.

The clinical trial is designed to evaluate the efficacy and safety of **riliprubart** in participants with refractory chronic inflammatory demyelinating polyneuropathy (CIDP). This is a Phase 3, double-blind, placebo-controlled study. The trial will involve randomization of participants to receive either riliprubart or a placebo, with the primary objective being to assess the efficacy of riliprubart relative to placebo as measured by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The trial is expected to commence recruitment on May 25, 2024, and conclude by October 12, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of CIDP according to the European Academy of Neurology/Peripheral Nerve Society guidelines, and refractoriness to immunoglobulin or corticosteroid therapy. Following successful screening, participants will be randomized and begin the intervention phase. The study will include multiple follow-up visits to monitor efficacy and safety outcomes, with assessments including changes in the INCAT disability score, grip strength, and the presence of treatment-emergent adverse events. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected duration of participant involvement in the trial is up to 48 weeks, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. Participants are required to adhere to contraceptive guidelines during and after the study to prevent pregnancy. The trial will also monitor the incidence and titer of anti-riliprubart antibodies as part of the safety assessments. The study aims to provide comprehensive data on the long-term efficacy and safety of riliprubart in this patient population.

The clinical trial involves the administration of **riliprubart**, a solution for injection, which is being evaluated for its efficacy and safety in participants with refractory chronic inflammatory demyelinating polyneuropathy. Riliprubart is provided in two pharmaceutical forms: a solution for injection in a pre-filled pen and a solution for injection. The pre-filled pen formulation is administered via **subcutaneous injection** with a maximum daily dose of 600 mg, and the treatment period can extend up to 48 weeks. The intravenous infusion formulation has a maximum daily dose of 50 mg/kg, with a treatment period limited to 1 week. The active substance, riliprubart, is a protein of other origin, developed by Sanofi Aventis Recherche et Développement (SAR). Participant compliance with the dosing schedule is monitored throughout the study.

The trial also includes the use of a placebo, which is a solution for injection provided in two forms: a vial and a prefilled pen (PFP). The placebo is administered to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is designed to match the riliprubart formulations in appearance and administration route, either subcutaneous injection or intravenous infusion, depending on the corresponding riliprubart form. The placebo serves as a comparator to evaluate the efficacy of riliprubart in improving the condition of participants as measured by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale.

The efficacy of riliprubart in participants with refractory chronic inflammatory demyelinating polyneuropathy (CIDP) will be assessed using several primary and secondary endpoints. The primary endpoints include the percentage of participants experiencing a response, the percentage of participants randomized to riliprubart with a lasting response, and the percentage of participants randomized to placebo who experience a response. Secondary endpoints will evaluate changes from baseline in various measures, including the Inflammatory Rasch-built Overall Disability Scale (I-RODS) score, the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, grip strength in kilopascals (dominant hand), and the Medical Research Council Sum Score (MRC-SS). Additional secondary endpoints include the percentage of participants refractory to immunoglobulins experiencing a response, changes from baseline in the EuroQol 5 Dimension, 5-Level Health Scale (EQ-5D-5L), and the Rasch-built modified fatigue severity scale (RT-FSS).

Data collection will occur at specified timepoints throughout the trial, including baseline and subsequent follow-ups, to monitor changes in these parameters. The INCAT disability scale will be a key tool for measuring efficacy, providing a standardized method to assess disability levels in participants. The trial will also monitor the incidence and titer of anti-riliprubart antibodies (ADA) and the number of participants with treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and adverse events of special interest (AESIs). These assessments will help determine the long-term efficacy and safety of riliprubart in the study population.