Efficacy and Safety of Subcutaneous Amlitelimab in Adults with Non-Responsive Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Phase 2a/b Study

The primary objective of this study is to evaluate the **efficacy** of amlitelimab compared to placebo in improving or attenuating gluten-induced changes in the intestinal mucosa of participants with non-responsive celiac disease (NRCD). This evaluation is conducted under two conditions: as an adjunct to a gluten-free diet and with background gluten exposure. The clinical relevance of this objective lies in its potential to offer a therapeutic option for patients with NRCD, a condition where symptoms persist despite adherence to a gluten-free diet, thereby addressing an unmet medical need.

Secondary objectives include:

• Evaluating the effect of amlitelimab versus placebo in controlling the severity of symptoms of celiac disease in participants with NRCD.
• Assessing the safety and tolerability of amlitelimab treatment in this patient population.
• Characterizing the pharmacokinetic profile of amlitelimab when administered by subcutaneous injection.
• Characterizing the immunogenicity of amlitelimab administered by subcutaneous injection.

The clinical trial involves a total of **376 participants** diagnosed with **coeliac disease**, specifically targeting individuals with non-responsive celiac disease (NRCD). The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on their physician-diagnosed celiac disease, with a documented history confirmed by medical records or a physician statement. All participants have attempted to maintain a gluten-free diet (GFD) for at least 12 consecutive months and are required to continue this diet throughout the study. The trial includes individuals who have an adequate understanding of a GFD and are willing to undergo all protocol assessments, including esophagogastroduodenoscopies with duodenal biopsies. During screening, participants must exhibit at least one gastrointestinal symptom of moderate or greater severity, related to gluten exposure, on at least three days out of any consecutive seven-day period. The trial population is inclusive of vulnerable groups, ensuring a comprehensive evaluation of the efficacy of amlitelimab versus placebo in improving or attenuating gluten-induced changes in intestinal mucosa.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of subcutaneous **amlitelimab** in adult patients with non-responsive **celiac disease**. The trial will be conducted in parallel groups and aims to assess the improvement or attenuation of gluten-induced changes in intestinal mucosa, serving as an adjunct to a gluten-free diet. The study is expected to commence recruitment on September 14, 2024, and conclude by April 10, 2029, with a total duration of approximately 148 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented history of biopsy-proven celiac disease, and compliance with a gluten-free diet. The screening will also assess the presence of moderate or greater severity gastrointestinal symptoms related to gluten exposure. Following successful screening, participants will be randomized to receive either amlitelimab or a matching placebo via subcutaneous injection.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status, adherence to the study protocol, and any treatment-emergent adverse events. These visits will include assessments such as esophagogastroduodenoscopies with duodenal biopsies, vital signs, and clinical laboratory evaluations. The primary endpoint is the change in villus height to crypt depth ratio from baseline to Week 28, while secondary endpoints include changes in gastrointestinal symptom severity scores and the incidence of treatment-emergent adverse events.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to discontinue participation. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and scientific integrity.

The clinical trial involves the administration of **Amlitelimab**, an investigational medication, to evaluate its efficacy and safety in adult patients with non-responsive celiac disease. **Amlitelimab** is provided as a **solution for injection in a pre-filled syringe**. The active substance, **Amlitelimab**, is a protein of other origin, developed by Sanofi Aventis Recherche et Développement (SAR). The medication is administered via **subcutaneous injection**. The dosing regimen includes a maximum daily dose of 500 mg, with a total maximum dose of 8500 mg over a treatment period of 148 days. The investigational product is not formulated for pediatric use.

In addition to the experimental treatment, a **placebo** is utilized in the study to serve as a comparator. The placebo is designed to match the appearance and administration route of the **Amlitelimab** solution, ensuring blinding in the randomized, double-blind, placebo-controlled study design. The placebo is administered subcutaneously, mirroring the administration schedule of the investigational product.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study aims to assess the impact of **Amlitelimab** on gluten-induced changes in the intestinal mucosa, with participants maintaining a gluten-free diet or experiencing background gluten exposure. The trial is conducted under strict regulatory standards to ensure the safety and well-being of all participants.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the change in **Villus Height to Crypt Depth Ratio (Vh:Cd)** from baseline to Week 28. This parameter is crucial for determining the impact of the treatment on intestinal mucosa in participants with non-responsive celiac disease. Secondary endpoints include changes in the Celiac Disease Symptom Diary (CDSD) Gastrointestinal (GI) symptom severity score, which will provide insights into symptom improvement. Additionally, the trial will monitor the percentage of participants experiencing treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and adverse events of special interest (AESI), as well as the percentage of participants with potentially clinically significant abnormalities in vital signs and clinical laboratory assessments. The percentage of participants who discontinue study treatment due to TEAEs will also be recorded. Serum amlitelimab concentrations will be measured at prespecified timepoints to assess drug exposure, and the incidence of anti-drug antibodies (ADAs) of amlitelimab will be evaluated to understand immunogenicity. These efficacy parameters will be collected and analyzed throughout the placebo-controlled treatment period and the long-term extension to ensure comprehensive assessment of the treatment's impact.