Evaluation of EXL01 for the Prevention of Post-Operative Recurrence in Crohn's Disease: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to compare the distribution of endoscopic **modified Rutgeerts scores** at 6 months post-surgery in patients with **Crohn's disease** (CD) treated with EXL01 versus those treated with placebo. This objective is clinically relevant as it aims to assess the efficacy of EXL01 in preventing post-operative recurrence of CD, which is a significant concern in the management of this chronic inflammatory condition.

Secondary objectives include:

• Evaluating the impact of EXL01 on severe endoscopic recurrence using the modified Rutgeerts score at 6 months post-surgery.
• Comparing the time to clinical relapse between EXL01 and placebo groups.
• Assessing disease-related symptoms and inflammatory markers post-surgery.
• Comparing endoscopic disease activity using the SES-CD score.
• Analyzing histological inflammation in the neoterminal ileum.
• Comparing the evolution of faecal- and mucosa-associated microbiota.
• Evaluating changes in health-related quality of life (HRQoL) using the SF-36 and IBDQ questionnaires.
• Assessing the impact of EXL01 on endoscopic remission at 6 months post-surgery.
• Evaluating the safety and tolerability of orally administered EXL01 post-surgery.

The clinical trial involves participants diagnosed with **Crohn's disease** with ileal involvement, either ileal only or ileocolonic, classified as L1 or L3 according to the Montreal classification. The study population includes both male and female subjects aged 18 years and older. Participants must have undergone an ileocecal resection or iterative ileo-colonic resection between 5 days to 5 weeks prior to randomization. The trial includes individuals scheduled to receive no treatment for Crohn's disease or anti-TNF agents in the 6 months following surgery. The trial population was selected based on these criteria, and it is noted that the study involves a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase 2**, multicenter, randomized, parallel-arm, placebo-controlled, double-blind study designed to evaluate the safety and target engagement of EXL01 in preventing post-operative recurrence of **Crohn's disease**. The trial will involve participants who have undergone ileocecal or iterative ileo-colonic resection and are scheduled to receive no treatment for Crohn's disease or anti-TNF agents in the six months following surgery. The study will compare the distribution of endoscopic modified Rutgeerts scores at six months post-surgery between patients treated with EXL01 and those receiving a placebo.

The trial is expected to commence recruitment on January 2, 2025, and conclude by January 1, 2027. Participants will be involved in the study for a maximum treatment period of 24 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits at Weeks 4, 12, and 24, with the end-of-study visit coinciding with the 24-week mark. During these visits, various assessments will be conducted, including endoscopic evaluations, clinical assessments, and laboratory tests to monitor disease activity and treatment effects.

Participants will be randomly assigned to receive either the investigational product, EXL01, or a matching placebo, administered orally in capsule form. The primary endpoint is the distribution of modified Rutgeerts scores at Week 24, evaluated by endoscopy with video capture and assessed by a blinded independent central review (BICR). Secondary endpoints include severe endoscopic recurrence, time to clinical relapse, and changes in various clinical and laboratory parameters.

Participant involvement may be terminated early if they experience adverse events that necessitate discontinuation of the study treatment or if they withdraw consent. The study is not classified as low intervention, and the investigational product is not a pediatric formulation. The trial is conducted under the sponsorship of the Groupe de Recherche sur les Maladies Inflammatoires et Digestives, with the investigational product being a live biotherapeutic product.

The clinical trial involves the administration of **EXL01**, an experimental medication designed to prevent post-operative recurrence of **Crohn's Disease**. **EXL01** is formulated as a **capsule** and is classified as a **Live Biotherapeutic Product**. The active substance, also named **EXL01**, is a structurally diverse substance. The medication is administered orally with a maximum daily dose of one capsule. The treatment period extends up to 24 weeks. The trial aims to evaluate the safety and target engagement of **EXL01** in comparison to a placebo. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes the use of a placebo, referred to as the **EXL01 matching Placebo**. This placebo is designed to mimic the appearance of the **EXL01** capsule but does not contain any active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered orally, following the same dosing schedule as the experimental medication, with a maximum daily dose of one capsule over a 24-week period. The use of the placebo allows for a controlled comparison to assess the efficacy and safety of **EXL01** in the prevention of post-operative recurrence of **Crohn's Disease**.

The efficacy of the investigational product, EXL01, in the prevention of post-operative recurrence of **Crohn's Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the distribution of modified Rutgeerts scores, categorized into four groups (i0, i1 - i2a, i2b, i3 - i4), at Week 24 or the end of treatment (EOT). This will be evaluated by endoscopy with video capture and assessed by a blinded independent central review (BICR).

Secondary endpoints include several measures: severe endoscopic recurrence at Week 24/EOT, defined as a modified Rutgeerts score of i3 or i4; time to clinical relapse, confirmed by endoscopy or imaging and assessed by BICR; and mean values and changes from baseline at Weeks 4, 12, and 24/EOT for the Crohn’s Disease Activity Index (CDAI) overall score, 2-item Patient-Reported Outcome Measure (PRO-2) scores, serum C-reactive protein (CRP) levels, and fecal calprotectin levels. Additional assessments include the SES-CD score, RHI score, and Geboes score at Week 24/EOT, evaluated from histopathology images and assessed by BICR.

Further analyses will involve 16S sequencing and shotgun metagenomics in fecal and tissue samples, as well as quantification of F. prausnitzii levels using qPCR/ddPCR. Patient-reported outcomes will be measured using the SF-36 and IBDQ scores. Endoscopic remission and recurrence of Crohn's Disease will also be evaluated at Week 24/EOT. The schedule for these assessments includes specific timepoints such as Weeks 4, 12, and 24/EOT, ensuring comprehensive data collection throughout the trial duration.