A 52-week randomized, double-blind, placebo-controlled, multi-center Phase 2b study with a 52-week blinded extension and an optional open-label extension—assessing the safety and efficacy of frexalimab, a CD40L-antagonist monoclonal antibody, for the preservation of pancreatic β-cell function in adults and adolescents with newly diagnosed type 1 diabetes on insulin therapy

The primary objective of this study is to demonstrate the **efficacy** of different doses of frexalimab, a CD40L antagonist monoclonal antibody, in comparison with placebo and in addition to standard of care (SOC) on endogenous insulin secretion in participants aged 12 to 21 years with newly diagnosed type 1 diabetes mellitus (T1D) over a 52-week period. This is clinically relevant as it aims to preserve pancreatic β-cell function, which is crucial in managing T1D and potentially reducing the need for exogenous insulin.

Secondary objectives include:

• Evaluating the efficacy of frexalimab in comparison to placebo and on top of SOC on glycemic control and endogenous insulin secretion in participants aged 12 to 21 years with newly diagnosed T1D.
• Assessing the safety and tolerability of frexalimab versus placebo in all participants.
• Characterizing the pharmacokinetics (PK) of frexalimab in all participants.
• Evaluating the potential for immunogenicity of frexalimab in all participants.
• Assessing the impact of frexalimab treatment on caregiver- and/or patient-reported clinical outcome measurements in all participants.

The clinical trial involves a total of **80 participants** diagnosed with **Type 1 diabetes mellitus**. The study population comprises both male and female subjects aged between **12 and 21 years**. Participants were selected based on their recent diagnosis of Type 1 diabetes, having initiated exogenous insulin replacement therapy no longer than 90 days prior to the screening visit. The trial includes individuals who are receiving standard of care treatments such as insulin hormone replacement therapy, either through multiple daily injections or continuous subcutaneous insulin infusion. Participants must also be positive for at least one Type 1 diabetes autoantibody and have random C-peptide levels of at least 0.2 nmol/L. The study population is considered vulnerable, and all participants are required to be vaccinated according to local schedules, with specific timing for live and non-live vaccines prior to randomization. Contraceptive use must align with local regulations for clinical study participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of **frexalimab**, a CD40L antagonist monoclonal antibody, in preserving pancreatic β-cell function in adults and adolescents with newly diagnosed **type 1 diabetes mellitus**. The trial consists of a 52-week treatment period followed by a 52-week blinded extension, making the overall trial duration approximately 104 weeks. Participants will be randomly assigned to receive either frexalimab or a matched placebo, administered via **intravenous (IV) or subcutaneous (SC)** routes, in addition to their standard insulin therapy.

The study will commence with an inclusion (screening) visit, where eligibility criteria will be assessed, including confirmation of type 1 diabetes diagnosis, initiation of insulin therapy within the last 90 days, and the presence of specific autoantibodies. Participants must also meet certain vaccination requirements and contraceptive use guidelines. Following the screening, eligible participants will undergo randomization and begin the treatment phase. Study visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetics, with primary endpoints including changes in C-peptide concentration and secondary endpoints assessing various metabolic and quality of life measures.

The expected length of participant involvement is up to 104 weeks, with conditions for early termination including the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the long-term effects of the treatment. Throughout the trial, the incidence of treatment-emergent adverse events, hypoglycemic and hyperglycemic episodes, and other safety parameters will be closely monitored to ensure participant safety and the integrity of the study data.

**Frexalimab** is the experimental medication being evaluated in this clinical trial. It is a **solution for injection** formulated by Sanofi Aventis Recherche et Développement (SAR). The active substance, frexalimab, is a protein of other origin, specifically a CD40L antagonist monoclonal antibody. The medication is administered either **intravenously (IV)** or **subcutaneously (SC)**. The maximum daily dose is 80 mg, with a total maximum dose of 1000 mg over the course of the treatment. The treatment period extends up to 104 weeks. Frexalimab is not a pediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **matched placebo** for comparison purposes. The placebo is designed to mimic the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo does not contain any active substance and is used to assess the efficacy and safety of frexalimab against a control group.

In addition to the experimental treatment and placebo, participants will continue to receive **standard-of-care therapy** for type 1 diabetes, which includes insulin therapy. The specific insulin products used are not detailed due to the diversity of available options at the ATC level. Insulin is administered via **subcutaneous injection** as part of the standard treatment regimen for managing blood glucose levels in individuals with type 1 diabetes.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to week 52 in the mean 2-hour mixed meal tolerance test (MMTT) stimulated **C-peptide** concentration. This measurement will evaluate the preservation of pancreatic β-cell function in participants with newly diagnosed type 1 diabetes.

Secondary endpoints include a variety of parameters measured at weeks 52 and 104. These include the time in range (70-180 mg/dL) and time in tight range (70-140 mg/dL) assessed by continuous glucose monitoring (CGM), changes in mean 2-hour MMTT stimulated C-peptide concentration calculated from the area under the curve (AUC), and the proportion of participants who remain C-peptide positive. Additional secondary endpoints involve the proportion of participants with partial remission, changes in insulin dose, HbA1c levels, and the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

Patient-reported outcomes will also be evaluated, including changes in the Pediatric Quality of Life (PedsQL) Diabetes Symptoms and Management domain scores, Problem Areas In Diabetes (PAID) total score, and Diabetes Treatment Satisfaction Questionnaires (DTSQs) scores. These assessments will be conducted at baseline, week 52, and week 104 to provide a comprehensive evaluation of the treatment's impact on both physiological and quality of life measures.