Efficacy, Safety, and Tolerability of KAN-101 in Celiac Disease: A Phase 2a Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the ability of **KAN-101** to attenuate gluten challenge (GC)-induced changes in duodenal histology, specifically by measuring changes in the villus-height:crypt depth (Vh:Cd) ratio after a 2-week GC. This is clinically relevant as it aims to evaluate the potential of KAN-101 to mitigate the histological damage caused by gluten exposure in individuals with celiac disease, which could lead to improved management of the condition.

Secondary objectives include:

• Examining the impact of KAN-101 on biomarker response, specifically interleukin-2 (IL-2), in peripheral blood following GC.
• Determining the effects of KAN-101 on histologic features, such as intraepithelial lymphocytes (IELs) density, in duodenum biopsies following a 2-week GC.
• Assessing the safety and tolerability of KAN-101 in participants with celiac disease.
• Evaluating the pharmacokinetics (PK) of multiple doses of KAN-101 in participants with celiac disease.

The clinical trial involves a total of **26 participants** diagnosed with **celiac disease**. The study population comprises adults aged 18 to 70 years, inclusive, encompassing both male and female subjects. Participants were selected based on a previously documented diagnosis of celiac disease, confirmed through positive serology and intestinal histology consistent with Marsh Type II or higher, indicating villous atrophy. All participants possess the HLA-DQ2.5 genotype and have adhered to a gluten-free diet for at least 12 months prior to the study, as self-reported. The trial includes individuals who are negative or weak positive for transglutaminase IgA and DGP-IgA/IgG during screening, with a screening intestinal biopsy demonstrating a villus-height:crypt depth ratio of 2.3 or higher. The study does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational product's efficacy across a diverse cohort.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of KAN-101 in participants with **celiac disease**. The trial aims to assess the ability of KAN-101 to attenuate gluten challenge-induced changes in duodenal histology, specifically measuring changes in the villus-height:crypt depth (Vh:Cd) ratio after a 2-week gluten challenge. The study will involve adult participants aged 18 to 70 years with a previously documented diagnosis of celiac disease, who have followed a gluten-free diet for at least 12 months prior to study entry. The trial is expected to commence recruitment on April 22, 2024, and conclude by December 12, 2024.

Participants will be involved in the study for a maximum treatment period of 7 days, with the total trial duration extending over several months to accommodate screening, treatment, and follow-up phases. The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as HLA-DQ2.5 genotype and a screening intestinal biopsy demonstrating a Vh:Cd ratio of 2.3 or higher. Following the screening, participants will undergo a baseline assessment before the initiation of the gluten challenge. Subsequent visits will include monitoring of primary and secondary endpoints, such as changes in Vh:Cd ratio and IL-2 levels, as well as the incidence of treatment-emergent adverse events and the presence of KAN-101 anti-drug antibodies.

The end-of-study visit will occur after the completion of the gluten challenge and final assessments, including esophagogastroduodenoscopy with biopsy, to evaluate changes from baseline. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial will utilize a solution for infusion as the route of administration for both the investigational product, KAN-101, and the placebo, sodium chloride. The study is not classified as a low-intervention trial and is categorized as a phase 2 therapeutic exploratory and confirmatory trial.

The clinical trial involves the administration of **KAN-101**, an investigational medication, to evaluate its efficacy, safety, and tolerability in participants with celiac disease. **KAN-101** is formulated as a **solution for infusion** and is administered intravenously. The active substance, **KAN-101**, is of polymer origin and is provided by ANOKION SA. The dosing regimen for **KAN-101** is set at a maximum daily dose of 0.6 mg/kg, with a total maximum dose of 0.6 mg/kg over a treatment period of up to 7 days. The administration schedule is designed to ensure participant compliance, with monitoring protocols in place to assess adherence to the dosing regimen.

In addition to the experimental treatment, the study includes the use of **sodium chloride** as a placebo. **Sodium chloride** is also provided as a **solution for infusion** and is administered intravenously. The placebo is matched in form and administration route to the investigational product to maintain the double-blind nature of the study. The dosing schedule for the placebo mirrors that of **KAN-101**, with a maximum daily dose of 0.6 mg/kg and a total maximum dose of 0.6 mg/kg over a 7-day period. Compliance with the placebo administration is similarly monitored to ensure the integrity of the study results.

The efficacy of KAN-101 in participants with **Celiac Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating changes from baseline in the villus-height:crypt depth (Vh:Cd) ratio, which will be measured by esophagogastroduodenoscopy (EGD) with biopsy after a 2-week gluten challenge (GC), specifically on Day 29. This endpoint aims to determine the ability of KAN-101 to attenuate GC-induced changes in duodenal histology.

Secondary endpoints include the assessment of interleukin-2 (IL-2) changes from Day 15 pre-GC to Day 15 post-GC, changes from baseline in intraepithelial lymphocyte (IEL) density in duodenum biopsy after the 2-week GC, and the incidence and severity of treatment-emergent adverse events (AEs) as per the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 or higher. Additionally, the incidence and titer of KAN-101 anti-drug antibodies (ADA) will be monitored, along with plasma concentration of KAN-101 and associated pharmacokinetic parameters such as AUCinf, AUClast, Cmax, Tmax, and t½.