ZED1227 shows histologic improvement in symptomatic celiac disease: Insights from the phase 2b CEC-004/CEL trial

Celiac disease is a chronic condition in which the body has an immune response to gluten, resulting in symptoms like diarrhoea, abdominal pain and fatigue. The phase 2b CEC-004/CEL study was a randomized, double-blind, placebo-controlled trial investigating ZED1227 for the treatment of symptomatic celiac disease.

In this interview, we spoke with Prof. Dr. Detlef Schuppan (Mainz University Medical Center, Germany) around the burden of symptomatic celiac disease, the mechanism of action of ZED1227, and the design and findings from the phase 2b CEC-004/CEL study.

The abstract “Clinical, Histologic And Safety Outcomes Of Zed1227 Treatment In Symptomatic Celiac Disease Patients: Results From The Phase 2b CEC-004/CEL Randomized Clinical Trial” was presented at UEG Week, 4–7 October, Berlin, Germany.

touchIMMUNOLOGY coverage of UEG Week 2025:

I’m Detlef Schuppan. I’m a Professor of Medicine currently at Mainz University in Germany, but also at Harvard Medical School as a Full Professor of Medicine, mainly in Germany though. My focus is with intestinal diseases, including celiac disease, IBD, but also liver disease, autoimmune diseases and cancer, which we support through our company in terms of some novel developments.

Q. Could you describe the burden of symptomatic celiac disease for patients?

That is a big discussion area because symptoms due to celiac disease can be very similar to other symptoms, for example due to irritable bowel syndrome (IBS), which is one of the exclusion criteria when you go towards therapies. We have a certain problem with patients with celiac disease on a well-controlled, gluten-free diet, who still have complaints, and that is difficult to separate from IBS-like symptoms.

Q. What is the mechanism of action of ZED1227?

ZED1227 is a highly specific drug for the enzyme tissue transglutaminase and it’s an irreversible inhibitor, based on a primary mechanism of action in celiac disease. The lamina propria of the gut is the largest immune system of the body lining the gut, and nutrients get into this immune system and are sensed normally as not dangerous, usually causing an immune suppressive, tolerogenic response. In patients with celiac disease, tissue transglutaminase activates gluten peptides to become immune stimulating and inflammatory by a chemical reaction of deamidation and cross-linking, causing them to be sensed like a dangerous, foreign antigen, like an invading bug for the body’s immune system.

What do we already know about the efficacy and safety of ZED1227 from the phase 2a CEC-003/CEL study?

The first study we did was a challenge study. Patients with celiac disease in histological and symptomatic condition were challenged voluntarily with an intermediate amount of ingested gluten for six weeks. They received drug in three concentrations or placebo, 40 roughly per group. We used the primary histological endpoint of a decrease of villous height to crypt depth (VH:CrD) in the duodenum, an indicator of gluten-induced damage, but also worsening of abdominal symptom. This drug prevented gluten-induced damage in these patients and alleviated minor symptoms that arose when patients consumed this amount of gluten. Safety was excellent.

Q. What were the aims, methodology, and inclusion criteria of the phase 2b CEC-004/CEL study?

We followed this up with the study CEC-004/CEL, which was a real-life study, enrolling patients with symptoms and significant, usually minor, measurable histological damage. After a run-in phase to rule out a placebo effect, which is important in these studies, patients were assigned to drug or placebo for 12 weeks and we chose the same endpoints, histology but now also including symptoms, so we had a combined endpoint. I will be presenting that in a couple of days, the results of the 400-patient study in roughly 100 centres in the world.

All the patients in these studies had an endoscopy with representative biopsies. Histological criteria included VH:CrD as a major criterion of gluten induced damage, and intraepithelial lymphocytosis, a secondary histological criterion, which represents inflammation. These biopsies were taken at baseline and at the end of therapy, 12 weeks in this case. At the same time, the patients filled in regular symptom scores. Thus, for study entry, patients had to fulfil certain moderate symptom scores, not minor symptoms or very severe symptoms, and symptom scores at the end of treatment were used together with histology as a combined endpoint.

So, patients had to fulfil both criteria, we wanted to confirm both the mechanism of action as well as clinical improvement – that’s what the FDA or EMA like to see, which is a bit complicated for celiac disease.

Q. What were the efficacy and safety findings?

Safety findings were excellent. They are not published yet, but I will be talking about this in a couple of days. For the efficacy findings, histology was improved in the highest dose group, in celiac patients with usually mild initial histological damage. Symptoms did not change.

This data is in a way promising, but on the other hand also points out that significant numbers of patients have symptoms due to something else, usually classified as IBS. We knew before that these patients overlap with patients that have minor to moderate complaints due to celiac disease. That’s the reason why we now are already following up with a very similar study called CEC-013/CEL, where patients receive a minor amount of gluten to keep the symptom baseline stable without worsening symptoms, also eliminating the problem of increasing compliance to an even more strict gluten-free diet during a clinical study.

Q. What is the clinical relevance of these findings?

The relevance is that the patients in a well-controlled study in celiac disease underlie the Hawthorne effect, a placebo effect. About 50% of the patients cannot yet be categorized as symptomatic due to celiac diseases when they present with IBS-like symptoms, which are associated with other food sensitivities, such as atypical food allergies or, for example, with post-viral IBS.