This is a Phase 2a/b, randomized, double-blind, placebo-controlled, parallel-group, 6-arm study to evaluate the efficacy and safety of amlitelimab in adult participants with non-responsive celiac disease (NRCD) who are on a gluten free diet (GFD) with and without simulated inadvertent gluten exposure (SIGE).

The primary purpose of this study is to demonstrate the efficacy of subcutaneous (SC) amlitelimab in male and female participants (aged 18 to 75 years, inclusive) with NRCD. The study will assess the effect of amlitelimab when compared to placebo on gluten induced changes in the intestinal mucosa as measured by the villous height to crypt depth (Vh:Cd) ratio. The effect of amlitelimab on participant-reported celiac signs and symptoms along with the safety, tolerability, and pharmacokinetics of amlitelimab will also be studied.

Study details include:

The study duration will be up to 48 weeks (including a 16-week safety follow-up period) with 10 visits for participants who opt not to enter the optional long-term extension.

The study duration will be up to 172 weeks (including an 8-week safety follow-up period) with 22 visits for participants who enter the optional long-term extension.

The double-blind placebo-controlled treatment duration will be up to 28 weeks.

Inclusion Criteria:

• Participants must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
• Participants with physician-diagnosed celiac disease with documented history of biopsy-proven celiac disease confirmed by medical records or physician statement.
• Participants who have self-reported attempt to maintain a GFD (and confirmed via questionnaire) for at least 12 consecutive months and must be willing to maintain their current diet for the duration of study participation.
• Participants have an adequate comprehension of a GFD as assessed by the Investigator.
• Participants willing to undergo all assessments in the protocol, including 2 esophagogastroduodenoscopies with duodenal biopsies.
• Participants who completed CDSD with ≥ 75% compliance from screening until randomization.
• During screening, participants must have at least one gastrointestinal symptom (i.e., diarrhea, abdominal pain, bloating, or nausea) of moderate or greater severity, as measured by the CDSD Gastrointestinal Domain, on at least 3 days out of any consecutive 7-day period considered by the investigator to be related to gluten exposure (i.e., due to celiac disease). The symptom can vary, but severity must be moderate or greater on three or more days. Participants must meet symptom criteria to undergo baseline esophagogastroduodenoscopy (EGD).

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• A diagnosis of any severe complication of celiac disease, such as refractory celiac disease type 1 (RCD I) requiring immune suppressive medication, or type 2 (RCD II), enteropathy associated T-cell lymphoma (EATL), ulcerative jejunitis, or recent (within 12 months of screening) GI perforation.
• Presence of other active inflammatory GI disorders, including but not limited to the following: inflammatory bowel disease, eosinophilic esophagitis, diverticulitis, helicobacter infection, gastroenteritis or colitis, and microscopic colitis (requiring treatment) in the 6 months before screening. A history of treated erosive esophagitis is not an exclusion. Abnormalities found during baseline EGD or biopsy that are consistent with an inflammatory GI disorder other than celiac disease are exclusionary.
• Presence of other systemic autoimmune diseases including scleroderma, psoriatic or rheumatoid arthritis, and lupus. Participants with thyroid disease that has been well-controlled for at least 6 months, prior to screening, and participants with well-controlled type 1 diabetes (glycosylated hemoglobin < 9 % and no hospitalization or emergency room visit in the last 12 months for hyperglycemia or hypoglycemia) can be included per investigator judgement.
• Known or suspected severe enteric infection (viral, bacterial, or parasitic) within 6 months before screening. Severe enteric infection is defined as requiring a visit to the emergency room, hospitalization, or treatment with antibiotics or anti-infectives due to infection. Non-enteric viral infections, either resolved or well-controlled are not exclusionary.
• Any active or chronic infection including helminthic infection requiring systemic treatment within 4 weeks prior to screening (1 week in the event of superficial skin infections).
• Known history of or suspected significant current immunosuppression or hyposplenism, including history of invasive opportunistic or invasive helminthic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration.
• Any malignancies or history of malignancies prior to enrollment (except for non-melanoma skin cancer that has been excised and completely cured for more than 5 years prior to enrollment).
• History of solid organ or stem cell transplant.
• Ongoing use, or use in the 3 months before screening, of medications known to cause villus abnormalities (eg, mycophenolate mofetil, azathioprine, methotrexate, olmesartan (other angiotensin receptor blockers are allowed), CTLA4 inhibitors, and PD-1/PD-L1 inhibitors).
• Ongoing chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) of more than 2 doses per week, except acetylsalicylic acid/aspirin ≤100 mg daily for prophylactic use.
• Any ongoing treatment with systemic immunosuppressants, systemic corticosteroids, or use of oral budesonide in the 12 weeks before screening.
• Ongoing use of over-the-counter digestive enzymes or supplements, other than lactase, including those for gluten digestion and oral pharmaceutical probiotic supplements. Probiotics in foods (e.g., yogurt) are permitted.
• Concurrent participation in any other clinical study, including non-interventional studies.
• Prior administration of investigational agents to treat celiac disease within 5 half-lives of any agent, or one year from any tolerogenic agent.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org