NEW PHARMACOLOGICAL THERAPIES FOR CELIAC DISEASE – A SYSTEMATIC REVIEW
Abstract
Background: Celiac disease is an immune-mediated condition caused by gluten in genetically susceptible individuals. Although a gluten-free diet is the basis of treatment, it is often difficult to maintain and may not fully prevent symptoms or intestinal damage.
Objective: This systematic review examines emerging non-dietary therapies for celiac disease, with emphasis on their mechanisms, clinical effectiveness, and safety.
Methods: A total of 23 peer-reviewed studies were analyzed, covering enzyme therapies, gluten sequestrants, tight junction modulators, immunotherapies, cytokine inhibitors, transglutaminase blockers, and probiotics.
Results: TAK-062 and ZED1227 emerged as the most promising candidates. TAK-062 showed strong gluten-degrading activity, while ZED1227 consistently reduced mucosal injury. Other enzymes, like latiglutenase, offered partial benefit, especially in seropositive patients. BL-7010 sequestered gliadin effectively in preclinical models. Larazotide acetate improved symptoms at low doses. Immunotherapies showed mixed outcomes—Nexvax2 failed in phase 2, while TAK-101 showed early potential. AMG 714 helped in refractory cases but lacked strong histological effects. Probiotics improved gut symptoms and microbiota balance, supporting their role as adjuncts.
Conclusions: While most therapies remain investigational, several show real potential as supplements to the gluten-free diet. Future research should focus on long-term outcomes and personalized approaches to improve disease management.
References
Bentley, D., Mannino, M., Manchester, M., Teixeira, P. C., Reis, B., Boyce, M., & Nagel, S. (2025). A randomized, double-blind, placebo-controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease. Clinical and Translational Science, 18(1), e13901. https://doi.org/10.1111/cts.13901
Catassi, C., Fabiani, E., Iacono, G., D’Agate, C., Francavilla, R., Biagi, F., Volta, U., Accomando, S., Picarelli, A., De Vitis, I., Pianelli, G., Gesuita, R., Carle, F., Mandolesi, A., Bearzi, I., & Fasano, A. (2007). A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease2. The American Journal of Clinical Nutrition, 85(1), 160–166. https://doi.org/10.1093/ajcn/85.1.160
Catassi, C., & Yachha, S. K. (2008). The Global Village of Celiac Disease. In A. Fasano, R. Troncone, & D. Branski (Eds.), Pediatric and Adolescent Medicine (pp. 23–31). KARGER. https://doi.org/10.1159/000128610
Cellier, C., Bouma, G., Van Gils, T., Khater, S., Malamut, G., Crespo, L., Collin, P., Green, P. H. R., Crowe, S. E., Tsuji, W., Butz, E., Cerf-Bensussan, N., Macintyre, E., Parnes, J. R., Leon, F., Hermine, O., Mulder, C. J., Jabri, B., Murray, J., … Raymond, R. (2019). Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: A phase 2a, randomised, double-blind, placebo-controlled, parallel-group study. The Lancet Gastroenterology & Hepatology, 4(12), 960–970. https://doi.org/10.1016/S2468-1253(19)30265-1
Daveson, A. J. M., Ee, H. C., Andrews, J. M., King, T., Goldstein, K. E., Dzuris, J. L., MacDougall, J. A., Williams, L. J., Treohan, A., Cooreman, M. P., & Anderson, R. P. (2017). Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study. EBioMedicine, 26, 78–90. https://doi.org/10.1016/j.ebiom.2017.11.018
Dotsenko, V., Tewes, B., Hils, M., Pasternack, R., Isola, J., Taavela, J., Popp, A., Sarin, J., Huhtala, H., Hiltunen, P., Zimmermann, T., Mohrbacher, R., Greinwald, R., Lundin, K. E. A., Schuppan, D., Mäki, M., Viiri, K., & CEC-3 Investigators. (2024). Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nature Immunology, 25(7), 1218–1230. https://doi.org/10.1038/s41590-024-01867-0
Francavilla, R., Piccolo, M., Francavilla, A., Polimeno, L., Semeraro, F., Cristofori, F., Castellaneta, S., Barone, M., Indrio, F., Gobbetti, M., & De Angelis, M. (2019). Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial. Journal of Clinical Gastroenterology, 53(3), e117–e125. https://doi.org/10.1097/MCG.0000000000001023
Goel, G., King, T., Daveson, A. J., Andrews, J. M., Krishnarajah, J., Krause, R., Brown, G. J. E., Fogel, R., Barish, C. F., Epstein, R., Kinney, T. P., Miner, P. B., Tye-Din, J. A., Girardin, A., Taavela, J., Popp, A., Sidney, J., Mäki, M., Goldstein, K. E., … Anderson, R. P. (2017). Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: Two randomised, double-blind, placebo-controlled phase 1 studies. The Lancet. Gastroenterology & Hepatology, 2(7), 479–493. https://doi.org/10.1016/S2468-1253(17)30110-3
Isola, J., Mäki, M., Hils, M., Pasternack, R., Viiri, K., Dotsenko, V., Montonen, T., Zimmermann, T., Mohrbacher, R., Greinwald, R., & Schuppan, D. (2023). The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment. International Journal of Molecular Sciences, 24(13), 10815. https://doi.org/10.3390/ijms241310815
Kelly, C. P., Murray, J. A., Leffler, D. A., Getts, D. R., Bledsoe, A. C., Smithson, G., First, M. R., Morris, A., Boyne, M., Elhofy, A., Wu, T.-T., Podojil, J. R., Miller, S. D., & TAK-101 Study Group. (2021). TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study. Gastroenterology, 161(1), 66-80.e8. https://doi.org/10.1053/j.gastro.2021.03.014
King, J. A., Jeong, J., Underwood, F. E., Quan, J., Panaccione, N., Windsor, J. W., Coward, S., deBruyn, J., Ronksley, P. E., Shaheen, A.-A., Quan, H., Godley, J., Veldhuyzen Van Zanten, S., Lebwohl, B., Ng, S. C., Ludvigsson, J. F., & Kaplan, G. G. (2020). Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. American Journal of Gastroenterology, 115(4), 507–525. https://doi.org/10.14309/ajg.0000000000000523
König, J., Holster, S., Bruins, M. J., & Brummer, R. J. (2017). Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. Scientific Reports, 7(1), 13100. https://doi.org/10.1038/s41598-017-13587-7
Lähdeaho, M.-L., Kaukinen, K., Laurila, K., Vuotikka, P., Koivurova, O.-P., Kärjä-Lahdensuu, T., Marcantonio, A., Adelman, D. C., & Mäki, M. (2014). Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology, 146(7), 1649–1658. https://doi.org/10.1053/j.gastro.2014.02.031
Lähdeaho, M.-L., Scheinin, M., Vuotikka, P., Taavela, J., Popp, A., Laukkarinen, J., Koffert, J., Koivurova, O.-P., Pesu, M., Kivelä, L., Lovró, Z., Keisala, J., Isola, J., Parnes, J. R., Leon, F., & Mäki, M. (2019). Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: A phase 2a, randomised, double-blind, placebo-controlled study. The Lancet Gastroenterology & Hepatology, 4(12), 948–959. https://doi.org/10.1016/S2468-1253(19)30264-X
Leffler, D. A., Kelly, C. P., Abdallah, H. Z., Colatrella, A. M., Harris, L. A., Leon, F., Arterburn, L. A., Paterson, B. M., Lan, Z. H., & Murray, J. A. (2012). A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. The American Journal of Gastroenterology, 107(10), 1554–1562. https://doi.org/10.1038/ajg.2012.211
Leffler, D. A., Kelly, C. P., Green, P. H. R., Fedorak, R. N., DiMarino, A., Perrow, W., Rasmussen, H., Wang, C., Bercik, P., Bachir, N. M., & Murray, J. A. (2015). Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: A randomized controlled trial. Gastroenterology, 148(7), 1311-1319.e6. https://doi.org/10.1053/j.gastro.2015.02.008
Ludvigsson, J. F., Leffler, D. A., Bai, J. C., Biagi, F., Fasano, A., Green, P. H. R., Hadjivassiliou, M., Kaukinen, K., Kelly, C. P., Leonard, J. N., Lundin, K. E. A., Murray, J. A., Sanders, D. S., Walker, M. M., Zingone, F., & Ciacci, C. (2013). The Oslo definitions for coeliac disease and related terms. Gut, 62(1), 43–52. https://doi.org/10.1136/gutjnl-2011-301346
Massironi, S., Franchina, M., Elvevi, A., & Barisani, D. (2024). Beyond the gluten-free diet: Innovations in celiac disease therapeutics. World Journal of Gastroenterology, 30(38), 4194–4210. https://doi.org/10.3748/wjg.v30.i38.4194
McCarville, J. L., Nisemblat, Y., Galipeau, H. J., Jury, J., Tabakman, R., Cohen, A., Naftali, E., Neiman, B., Halbfinger, E., Murray, J. A., Anbazhagan, A. N., Dudeja, P. K., Varvak, A., Leroux, J.-C., & Verdu, E. F. (2014). BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity. PloS One, 9(11), e109972. https://doi.org/10.1371/journal.pone.0109972
Murray, J. A., Syage, J. A., Wu, T.-T., Dickason, M. A., Ramos, A. G., Van Dyke, C., Horwath, I., Lavin, P. T., Mäki, M., Hujoel, I., Papadakis, K. A., Bledsoe, A. C., Khosla, C., Sealey-Voyksner, J. A., & CeliacShield Study Group. (2022). Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge. Gastroenterology, 163(6), 1510-1521.e6. https://doi.org/10.1053/j.gastro.2022.07.071
Nikoloudaki, O., Celano, G., Polo, A., Cappello, C., Granehäll, L., Costantini, A., Vacca, M., Speckmann, B., Di Cagno, R., Francavilla, R., De Angelis, M., & Gobbetti, M. (2024). Novel probiotic preparation with in vivo gluten-degrading activity and potential modulatory effects on the gut microbiota. Microbiology Spectrum, 12(7), e0352423. https://doi.org/10.1128/spectrum.03524-23
Pultz, I. S., Hill, M., Vitanza, J. M., Wolf, C., Saaby, L., Liu, T., Winkle, P., & Leffler, D. A. (2021). Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease. Gastroenterology, 161(1), 81-93.e3. https://doi.org/10.1053/j.gastro.2021.03.019
Raehsler, S. L., Choung, R. S., Marietta, E. V., & Murray, J. A. (2018). Accumulation of Heavy Metals in People on a Gluten-Free Diet. Clinical Gastroenterology and Hepatology, 16(2), 244–251. https://doi.org/10.1016/j.cgh.2017.01.034
Salden, B. N., Monserrat, V., Troost, F. J., Bruins, M. J., Edens, L., Bartholomé, R., Haenen, G. R., Winkens, B., Koning, F., & Masclee, A. A. (2015). Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. Alimentary Pharmacology & Therapeutics, 42(3), 273–285. https://doi.org/10.1111/apt.13266
Santonicola, A., Soldaini, C., & Ciacci, C. (2025). New therapies in celiac disease. Current Opinion in Gastroenterology, 41(3), 124–131. https://doi.org/10.1097/MOG.0000000000001080
Schuppan, D., Mäki, M., Lundin, K. E. A., Isola, J., Friesing-Sosnik, T., Taavela, J., Popp, A., Koskenpato, J., Langhorst, J., Hovde, Ø., Lähdeaho, M.-L., Fusco, S., Schumann, M., Török, H. P., Kupcinskas, J., Zopf, Y., Lohse, A. W., Scheinin, M., Kull, K., … CEC-3 Trial Group. (2021). A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. The New England Journal of Medicine, 385(1), 35–45. https://doi.org/10.1056/NEJMoa2032441
Stefanolo, J. P., Segura, V., Grizzuti, M., Heredia, A., Comino, I., Costa, A. F., Puebla, R., Temprano, M. P., Niveloni, S. I., de Diego, G., Oregui, M. E., Smecuol, E. G., de Marzi, M. C., Verdú, E. F., Sousa, C., & Bai, J. C. (2024). Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet. World Journal of Gastroenterology, 30(11), 1545–1555. https://doi.org/10.3748/wjg.v30.i11.1545
Syage, J. A., Murray, J. A., Green, P. H. R., & Khosla, C. (2017). Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet. Digestive Diseases and Sciences, 62(9), 2428–2432. https://doi.org/10.1007/s10620-017-4687-7
Tack, G. J., van de Water, J. M. W., Bruins, M. J., Kooy-Winkelaar, E. M. C., van Bergen, J., Bonnet, P., Vreugdenhil, A. C. E., Korponay-Szabo, I., Edens, L., von Blomberg, B. M. E., Schreurs, M. W. J., Mulder, C. J., & Koning, F. (2013). Consumption of gluten with gluten-degrading enzyme by celiac patients: A pilot-study. World Journal of Gastroenterology, 19(35), 5837–5847. https://doi.org/10.3748/wjg.v19.i35.5837
Truitt, K. E., Daveson, A. J. M., Ee, H. C., Goel, G., MacDougall, J., Neff, K., & Anderson, R. P. (2019). Randomised clinical trial: A placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease. Alimentary Pharmacology & Therapeutics, 50(5), 547–555. https://doi.org/10.1111/apt.15435
Wu, X., Qian, L., Liu, K., Wu, J., & Shan, Z. (2021). Gastrointestinal microbiome and gluten in celiac disease. Annals of Medicine, 53(1), 1797–1805. https://doi.org/10.1080/07853890.2021.1990392
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Copyright (c) 2025 Mateusz Myśliwiec, Tytus Tyralik, Maciej Karwat, Julia Kular, Oliwia Malec, Justyna Niebylecka, Izabella Michalska, Natalia Glanc, Dominik Sendecki, Grzegorz Zalewski

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