Why a Strict GFD Is Not Enough for Many Patients
While a gluten-free diet (GFD) remains the cornerstone of celiac disease management, it is often insufficient for full disease control.
Clinical studies suggest that up to 30% of patients continue to experience symptoms or demonstrate persistent villous atrophy despite strict adherence. Causes range from inadvertent gluten exposure, due to cross-contamination or mislabeling, to incomplete mucosal healing in sensitive individuals. These patients may suffer from bloating, diarrhea, abdominal pain, fatigue, and nutrient malabsorption, which significantly impact quality of life. Even among asymptomatic patients, failure to achieve histological remission is associated with increased long-term risk of complications such as osteoporosis, infertility, and enteropathy-associated T-cell lymphoma.
Moreover, the social and financial burdens of a lifelong GFD can affect adherence. As a result, there is growing clinical demand for adjunctive or alternative therapies that can protect the mucosa, mitigate symptoms from trace gluten ingestion, or eventually induce immune tolerance.
Enzymatic Therapies – Latiglutenase & Other Endopeptidases
Enzymatic therapy represents one of the most practical and near-term approaches to supplementing the gluten-free diet.
These agents aim to degrade immunogenic gluten peptides in the stomach or upper small intestine, thereby preventing them from triggering an inflammatory response in the gut mucosa.
Latiglutenase (IMGX003), an oral mixture of two proteases engineered to cleave the proline- and glutamine-rich sequences of gluten, was the first to reach advanced clinical development. Phase 2 trials yielded inconsistent results: while histological outcomes were limited, symptomatic improvement—particularly in patients with ongoing gastrointestinal symptoms—was observed in some subgroups. The agent is currently not in active phase 3 development, but newer enzyme candidates with enhanced acid stability and activity in gastric conditions are under investigation.
Other endopeptidases in development, such as TAK-062 and KumaMax-derived therapies, offer improved specificity and durability in degrading toxic epitopes. These enzymes are being studied for as-needed use, such as when patients risk inadvertent gluten exposure in social settings, restaurants, or travel.
Enzymatic therapy is not expected to replace the GFD but could serve as an adjunct to minimize mucosal damage and improve quality of life for patients struggling with dietary compliance or ongoing symptoms.
tTG2 Inhibitors – Proof-of-Concept for ZED1227
Among the most promising non-dietary therapies for celiac disease are tissue transglutaminase 2 (tTG2) inhibitors, which target a central enzymatic step in disease pathogenesis.
In genetically susceptible individuals, gluten peptides are deamidated by tTG2 in the small intestine, enhancing their immunogenicity and promoting recognition by HLA-DQ2/8-restricted T cells. Inhibiting this enzyme therefore interrupts the inflammatory cascade at an early stage.
ZED1227, developed by Dr. Falk Pharma, is the first-in-class selective tTG2 inhibitor to demonstrate clinical efficacy. It is formulated for local action in the gut, minimizing systemic exposure. In a phase 2, double-blind, placebo-controlled trial published in The New England Journal of Medicine (2021), 160 adults with biopsy-confirmed celiac disease were randomized to receive ZED1227 at varying doses or placebo, alongside a daily gluten challenge of 3 grams for six weeks.
Results showed a dose-dependent reduction in mucosal damage, with the highest dose group exhibiting significantly less villous atrophy and crypt hyperplasia compared to placebo. Importantly, intraepithelial lymphocyte counts, a hallmark of immune activation, were also lower. While clinical symptom scores improved modestly, the primary benefit was histologic protection, suggesting that ZED1227 may be particularly useful for asymptomatic patients at risk of long-term complications.
The treatment was generally well tolerated, with most adverse events being mild and gastrointestinal in nature. Crucially, systemic tTG2 inhibition was not observed, supporting the safety of gut-restricted action.
Phase 3 trials are now underway to evaluate longer-term safety, symptom control, and quality of life outcomes in real-world gluten exposure settings, rather than standardized challenges. If successful, ZED1227 could become the first approved pharmacologic agent for celiac disease, offering mucosal protection for patients who inadvertently ingest small amounts of gluten despite maintaining a GFD.
Immune Tolerance Strategies: TPM502, Antigen-Specific Therapies
Beyond enzymatic and barrier-based strategies, researchers are investigating therapies that aim to retrain the immune system to tolerate gluten.
These antigen-specific immunotherapies seek to restore immune homeostasis rather than merely block downstream inflammation, offering the potential for long-term remission or even cure.
TPM502 is a nanoparticle-based immunotherapy developed by COUR Pharmaceuticals. It encapsulates gliadin peptides and is designed to be taken up by antigen-presenting cells (APCs) in the liver and spleen, thereby promoting tolerogenic pathways. In a phase 1b trial, TPM502 showed that repeated intravenous dosing led to reduced gluten-specific CD4+ T-cell activation and favorable safety outcomes, with no serious adverse events reported. While early, these findings support further development of nanoparticle-induced tolerance in celiac disease.
Other investigational approaches include peptide vaccines, such as Nexvax2, which previously advanced to phase 2 before development was discontinued due to lack of efficacy. Lessons from that program have informed more targeted immunotherapy designs, including selective delivery of dominant gliadin epitopes and combination strategies with immunomodulators.
Efforts are also underway to explore dendritic cell modulation and engineered T-cell receptor (TCR) therapies, though these remain preclinical. Compared to enzymes or tTG2 inhibitors, immune therapies involve longer development timelines and more complex trial designs, but they hold promise for a disease-modifying approach that may allow patients to reintroduce gluten safely in the future.
Regulatory Landscape & Patient-Reported Outcome Endpoints
As investigational therapies for celiac disease advance toward late-stage trials, regulatory expectations have shifted to better reflect the real-world experience of patients.
Both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) now emphasize a combination of histologic endpoints (e.g., Marsh classification, villous height–crypt depth ratio) and patient-reported outcome measures (PROMs) to assess therapeutic benefit. Validated tools like the Celiac Disease Symptom Diary (CDSD) and Patient Global Impression of Severity (PGI-S) have been integrated into recent trials to capture daily symptom fluctuation, gastrointestinal distress, and quality-of-life impact. These instruments are especially relevant for therapies intended to support the gluten-free diet rather than replace it.
Moreover, regulatory agencies increasingly support adaptive trial designs, real-world gluten exposure models, and surrogate markers of immune activation. This evolving framework is enabling faster evaluation of drug candidates, particularly those aimed at mitigating the burden of inadvertent gluten exposure.
Clinical Implications and Timeline to Market
Non-dietary therapies for celiac disease are no longer speculative—several are approaching potential regulatory approval.
Enzymatic treatments and gut-restricted tTG2 inhibitors like ZED1227 are the most advanced, with phase 3 trials underway and possible market entry projected between 2025 and 2027. These agents are likely to be approved as adjuncts to a gluten-free diet, especially for patients with persistent symptoms, incomplete mucosal healing, or risk of accidental gluten exposure.
Immune tolerance therapies, while conceptually transformative, remain in earlier development. Agents like TPM502 may take several more years to reach phase 3, given the complexity of immune modulation and the need for longer follow-up.
Clinicians should begin preparing to stratify patients by need and risk—those with high dietary burden, psychosocial impact, or refractory histology may benefit most from early adoption. As therapeutic options expand, patient education and shared decision-making will become increasingly central to care.
Key Practice Points
Non-dietary therapies may soon complement the gluten-free diet, especially for symptomatic patients with trace exposure, with ZED1227 and enzymatic therapies leading development.
- Non-dietary therapies may soon complement the gluten-free diet, especially for symptomatic patients with trace exposure.
- ZED1227 and enzymatic therapies are furthest in development and may reach market within the next 2–3 years.
- Long-term remission and immune tolerance remain aspirational goals, with nanoparticle therapies and antigen-specific approaches still in early trials.
References
- Schuppan, D., Mäki, M., Lundin, K. E. A., Isola, J., Friesing-Sosnik, T., Taavela, J., … & Ciclitira, P. J. (2021). Randomized trial of a transglutaminase 2 inhibitor for celiac disease. New England Journal of Medicine, 384(18), 1737–1747. https://doi.org/10.1056/NEJMoa2032441
- Celiac Disease Foundation. (2025). Future therapies for celiac disease. Retrieved from https://celiac.org/about-celiac-disease/future-therapies-for-celiac-disease/?utm_source=chatgpt.com
- Silvester, J. A., MacDonald, A., & Kelly, C. P. (2025). Emerging therapies and late-stage pipeline for celiac disease. Frontiers in Immunology, 16, Article 11970589. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970589/
- Leffler, D. A., & Schuppan, D. (2024). Patient-reported outcomes and histologic endpoints in celiac disease clinical trials. American Journal of Gastroenterology, 119(4), 572–580. https://doi.org/10.14309/ajg.0000000000002147
- Murray, J. A., & Lebwohl, B. (2022). Enzymatic therapies and the future of adjunct treatment in celiac disease. Gastroenterology Clinics of North America, 51(1), 117–130. https://doi.org/10.1016/j.gtc.2021.09.007