Beyond the gluten-free diet: Innovations in celiac disease therapeutics

Table 1 Phase 2 studies exploring quantitative strategies in patients with celiac disease

NCT number	Study title	Study status (completion date)	Drug	Mechanism	Primary outcome measures	Sponsor	Phases
NCT01990885	Safety and systemic exposure study of BL-7010 in patients with well-controlled CD	Completed (October 2014)	BL-7010 vs placebo	BL-7010 interacts with α-gliadin and prevents the formation of immunogenic and cytotoxic peptides	Incidence of adverse events. For part 1, subjects were followed for up to 7 weeks from time of first administration. For part 2, subjects were followed for up to 4 weeks from time of first administration	BioLineRx, Ltd.	Phase 1, Phase 2
NCT03707730 AGY-010	A randomized, double-blind, placebo-controlled, crossover trial to evaluate safety and efficacy of AGY in CD	Unknown (December 2022)	AGY vs placebo	IgY antibody put into capsule form (AGY), produced from the egg yolks of superimmunized laying hens	Safety (adverse events, laboratory results, symptoms). tTGA levels measured at each visit. CD- related symptoms 14 weeks	Igy Inc.	Phase 2
NCT01917630	Evaluation of the efficacy and safety of ALV003 in symptomatic patients with CD	Completed (June 2015)	Latiglutenase (ALV003) vs placebo	ALV003 is a mixture of two recombinant gluten-specific proteases to contribute to the degradation of gluten into non-immunogenic fragments	Efficacy: Intestinal mucosal morphometry, change in Vh:Cd between baseline and week 12	Alvine Pharmaceuticals Inc.	Phase 2
NCT01255696	Safety and efficacy of varying methods of ALV003 administration for the treatment of CD	Completed (June 2011)	Latiglutenase (ALV003) vs placebo	ALV003 is a mixture of two recombinant gluten-specific proteases to contribute to the degradation of gluten into non-immunogenic fragments	Efficacy: Intestinal mucosal morphology. Safety: Tolerability of ALV003, safety evaluated at 6 weeks	Alvine Pharmaceuticals Inc.	Phase 2
NCT00959114	Safety and efficacy of ALV003 for the treatment of CD	Completed (October 2010)	Latiglutenase (ALV003)	ALV003 is a mixture of two recombinant gluten-specific proteases to contribute to the degradation of gluten into non-immunogenic fragments	Efficacy: Intestinal mucosal morphology. Safety: Tolerability of ALV003 at 6 weeks	Alvine Pharmaceuticals Inc.	Phase 2
NCT01255696	Safety and efficacy of ALV003 for the treatment of CD	Completed (June 2011)	Latiglutenase (ALV003)	ALV003 is a mixture of two recombinant gluten-specific proteases to contribute to the degradation of gluten into non-immunogenic fragments	Efficacy: Intestinal mucosal morphology. Safety: Tolerability of ALV003 at 6 weeks	Alvine Pharmaceuticals Inc.	Phase 2
NCT03585478	Latiglutenase (IMGX003) as a treatment for CD	Completed (January 22, 2021)	Latiglutenase (IMGX003) vs placebo	A combination of ALV001 and ALV002, a Sphingomonas capsulata PEP that degrade gluten proteins and reduces the immunogenic potential of gluten	The primary efficacy endpoint of this study is histologic protection as measured by EGD (Vh:Cd) at 6 weeks	Immunogenics, LLC	Phase 2
NCT04243551	Prospective, randomized, double-blind, placebo-controlled, crossover study of latiglutenase (IMGX003) in symptomatic patients with CD	Active, not recruiting (December 2023)	Latiglutenase vs placebo	A combination of ALV001 and ALV002, a Sphingomonas capsulata PEP that degrade gluten proteins and reduces the immunogenic potential of gluten	The primary efficacy endpoint of this study is the mean percent reduction in symptom severity relative to placebo at 6 months	Immunogenics, LLC	Phase 2
NCT04839575	Study of latiglutenase (IMGX003) in T1D/CD patients	Terminated (December 19 2022)	DRUG: Latiglutenase vs placebo	A combination of ALV001 and ALV002, a Sphingomonas capsulata PEP that degrade gluten proteins and reduces the immunogenic potential of gluten	The primary efficacy endpoint of this study is absolute mean reduction in symptom severity relative to placebo at 6 months	Immunogenics LLC	Phase 2
NCT05353985	A study of TAK-062 in treatment of active CD in participants attempting a gluten-free diet	Recruiting (May 6, 2025)	TAK-062 with or without simulated inadvertent gluten exposure gluten-bar	Third-generation enzyme with the ability to degrade > 99% of gluten and gluten peptides	Change in weekly CD symptom diary gastrointestinal symptom severity score from baseline (week 1) to week 12	Takeda	Phase 2
NCT00810654	Effect of Aspergillus Niger prolyl endoprotease (AN-PEP) enzyme on the effects of gluten ingestion in patients with CD	Completed (2009-12)	AN-PEP 160 PPU daily for 2 weeks	An enzyme that degrades both whole gluten and gluten peptides into non-immunogenic residues within minutes	Histopathological changes according to the modified marsh criteria. The presence of CD-specific antibodies (EMA, tTGA, gliadin) (1 week before start, and 2 and 6 weeks after start)	Amsterdam UMC, location VUmc	Phase 1, phase 2

AN-PEP: Aspergillus Niger prolyl endoprotease; CD: Celiac disease; EGD: Esophagogastroduodenoscopy; EMA: Endomysial antibodies; IgY: Avian immunoglobulin Y; PEP: Prolyl endopeptidase; T1D: Type 1 diabetes; tTGA: Tissue transglutaminase IgA; Vh:Cd: Villous height to crypt depth ratio.

Table 2 Phase 2 studies exploring gluten tolerance strategies in patients with celiac disease

NCT number (Acronym)	Study title	Study status (Completion date)	Drug	Mechanism	Primary outcome measures	Sponsor	Phases
NCT06001177 (SynCeD)	A study of efficacy, safety, and tolerability of KAN-101 in people with CD	Recruiting (June 2025)	KAN-101 vs placebo	KAN-101 acts by re-educating T cells, or tolerizing them, so they do not respond to gluten antigens	Changes from baseline in Vh:Cd as assessed by esophagogastroduodenoscopy with biopsy after 2-week gluten challenge	Kanyos Bio, Inc., a wholly-owned subsidiary of Anokion SA	Phase 2
NCT05574010 (ACeD-it)	A study of safety, tolerability, pharmacodynamics, and pharmacokinetics of KAN-101 in CD	Recruiting (April 2, 2025)	Part A: Multiple ascending dose of KAN-101. Parts B and C: Participants will be randomized 1:1:1:1 to placebo and 3 treatment groups with KAN-101 doses based on information obtained from part A	KAN-101 acts by re-educating T cells, or tolerizing them, so they do not respond to gluten antigens	Severity of TEAEs assessed by common terminology criteria for adverse events (part A) at 28 days. Efficacy assessed by change in magnitude of IL-2 response pre- and post-germinal center (part B), baseline to day 15	Kanyos Bio, Inc., a wholly owned subsidiary of Anokion SA	Phase 1, Phase 2
NCT03738475	Study of the safety, pharmacodynamic, efficacy, and PK of TAK-101 in subjects with CD	Completed (July 22, 2019)	TAK-101 vs placebo	TAK-101, gliadin encapsulated in nanoparticles to induce gluten-specific tolerance	Change from baseline in interferon gamma spot-forming units based on results of a gliadin-specific enzyme-linked immunospot on day 20	Takeda	Phase 2
NCT04530123	Dose-ranging study of the efficacy and safety of TAK-101 for prevention of gluten-specific T-cell activation in participants with CD on a gluten-free diet	Active, not recruiting (May 29, 2024)	TAK-101 with or without gluten	TAK-101, gliadin encapsulated in nanoparticles to induce gluten-specific tolerance	Change from baseline in interferon gamma spot-forming units based on results of a gliadin-specific enzyme-linked immunospot on day 20	Takeda	Phase 2
NCT05660109	A study to assess the safety of TPM502 in adults with CD	Recruiting (May 30, 2024)	Drug: TPM502. Other: Placebo	TPM502 is a mixture of nanoparticles carrying gluten-specific antigenic peptides to the liver, to induce gluten tolerization	Incidence, severity, causality, and outcomes of TEAEs throughout the study, on average 43 days	Topas Therapeutics GmbH	Phase 2
NCT03644069	A study of the safety, efficacy and tolerability of Nexvax-2 in patients with CD	Unknown (September 2019)	Nexvax2 vs placebo	Nexvax2 is a therapeutic vaccine that desensitizes and induces gluten tolerance	Efficacy of Nexvax2 in reducing CD-associated GI symptoms, measured by the CD patient-reported outcome between baseline and the day of the first masked food challenge containing gluten	ImmusanT, Inc.	Phase 2

CD: Celiac disease; GI: Gastrointestinal; IL: Interleukin; TEAEs: Treatment-emergent adverse events; Vh:Cd: Villous height to crypt depth ratio.

Table 3 Phase 2 studies on tight junction modulator (larazotide acetate) in patients with celiac disease

NCT number	Study title	Study status (Completion date)	Drug	Mechanism	Primary outcome measures	Sponsor	Phases
NCT00492960	Study to assess the efficacy of larazotide acetate for the treatment of CD	Completed (March 2009)	Larazotide acetate vs placebo (dietary supplement: 900 mg gluten)	Larazotide acetate intervenes by blocking the zonulin receptors and thus preventing the dissolution of the tight junction and the associated increase in intestinal permeability	Efficacy of multiple doses larazotide acetate in preventing intestinal permeability changes induced by a 6-week gluten challenge on days 7, 21, 35, 49, and 56	9 Meters Biopharma Inc.	Phase 2
NCT00362856	Safety and tolerability study of larazotide acetate in patients with CD	Completed (March 6, 2007)	Larazotide vs placebo	Larazotide acetate intervenes by blocking the zonulin receptors and thus preventing the dissolution of the tight junction and the associated increase in intestinal permeability	Safety endpoints assessed were adverse events. Measured at screening and on days 0, 7, 14, and 21 (‘End of Study’). Efficacy of multiple dose levels of larazotide acetate in preventing intestinal permeability changes induced by gluten challenge, measured as urinary LAMA ratio the day 0-to-day 14 change	9 Meters Biopharma, Inc.	Phase 2
NCT01396213	A double-blind placebo-controlled study to evaluate larazotide acetate for the treatment of CD	Completed (August 20, 2013)	Larazotide vs placebo	Larazotide acetate intervenes by blocking the zonulin receptors thus preventing the dissolution of the tight junction and the associated increase in intestinal permeability	The primary efficacy endpoint was the changes in the average on-treatment (baseline to week 12) score of the CD gastrointestinal symptom rating scale	9 Meters Biopharma, Inc.	Phase 2
NCT00620451	Randomized, double-blind, placebo-controlled study of larazotide acetate in subjects with active CD	Completed (December 2009)	Larazotide acetate vs placebo	Larazotide acetate intervenes by blocking the zonulin receptors and thus preventing the dissolution of the tight junction and the associated increase in intestinal permeability	Assess the efficacy of larazotide acetate. Remission was defined as an improvement in the Vh:Cd ratio obtained by duodenojejunal biopsy at baseline and day 56	9 Meters Biopharma, Inc.	Phase 2
NCT00889473	Study of the efficacy of larazotide acetate in CD	Completed (April 2010)	Larazotide acetate vs placebo (dietary supplement: gluten 900 mg)	Larazotide acetate intervenes by blocking the zonulin receptors and thus preventing the dissolution of the tight junction and the associated increase in intestinal permeability	Response to gluten at 6 weeks	9 Meters Biopharma, Inc.	Phase 2

CD: Celiac disease; LAMA: Lactulose to mannitol; Vh:Cd: Villous height to crypt depth ratio.

Table 4 Phase 2 studies exploring lymphocyte trafficking and homing inhibitors

NCT number	Study title	Study status (Completion date)	Drug	Mechanism	Primary outcome measures	Sponsor	Phases
NCT00540657	A Phase 2 study of CCX282-B in patients with CD	Completed (July 2008)	CCX282 vs placebo	CCX282-B is a chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine	Evaluation of the effect of CCX282-B compared to placebo on the Vh:Cd ratio of small intestinal biopsy specimens taken from patients with CD, before and after gluten exposure	ChemoCentryx	Phase 2
NCT02929316	Vedolizumab induction may prevent celiac enteritis	Terminated (October 5, 2018)	Vedolizumab	Vedolizumab is a monoclonal antibody against integrin α4β7 that inhibit lymphocyte homing to the bowel	Histopathologic remission following induction with vedolizumab (defined as negative CD antibodies and normal duodenal biopsies) at 12 weeks	AGA Clinical Research Associates, LLC	Phase 2
NCT04806737	A Phase 2a, double-blind, randomized, placebo-controlled study on the efficacy and tolerability of a 14-day treatment with teriflunomide vs placebo in subjects with coeliac disease undergoing a 3-day gluten challenge	Unknown (August 15, 2022)	Oral teriflunomide vs placebo	Teriflunomide inhibits de novo synthesis of pyrimidine, performing a cytostatic effect on lymphocyte proliferation	Check the adaptive T-cell activation, evaluating the expression of CD38 on HLA-DQ: Gluten tetramer-positive T cells on peripheral blood on day 4 after a 3-day gluten challenge	Oslo University Hospital	Phase 1-phase 2
NCT02637141	A Phase 2a, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of AMG 714 in adult patients with CD	Completed (May 2, 2017)	AMG 714 vs placebo	AMG 714 is a monoclonal antibody an anti-IL-15, a pivotal cytokine in CD pathogenesis	Percent change from baseline in Vh:CD. To evaluate the attenuation of the effects of gluten exposure after 10 weeks of gluten challenge at week 12	Amgen	Phase 2
NCT02633020	A Phase 2a, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of AMG 714 in adult patients with type II refractory CD	Completed (May 2, 2017)	AMG 714 vs placebo	AMG 714 is a monoclonal antibody anti-IL-15	Percent change from baseline in the percentage of aberrant intestinal intraepithelial lymphocytes with respect to all intraepithelial lymphocytes at baseline and week 12	Amgen	Phase 2
NCT04424927 proactive	A Phase 2b, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of PRV-015 in adult patients with non-responsive CD as an adjunct to a gluten-free diet	Recruiting (August 31, 2024)	PRV-015 vs placebo	PRV-015 is a monoclonal antibody against IL-15, a pivotal cytokine in CD pathogenesis	Efficacy of PRV-015 in attenuating the symptoms of CD in non-responsive CD as measured by the celiac disease patient-reported outcome questionnaire at 24 weeks	Provention Bio, Inc.	Phase 2
NCT05636293	Double-blind, placebo-controlled trial to establish safety and efficacy of ritlecitinib to prevent gluten-induced celiac enteropathy and symptoms in CD patients in remission	Recruiting (January 1, 2025)	Ritlecitinib vs placebo	Ritlecitinib is a selective Janus kinase 3 inhibitors that prevent lymphocyte activation and proliferation	Change in small intestinal histology based on Vh:Cd ratio to characterize the gluten-challenge induced changes. Patient-reported outcomes defined as CD PRO to evaluate gluten challenge-triggered symptoms. Through study completion, average of 1 year	Massachusetts General Hospital	Phase 2

CD: Celiac disease; CCR9: C-C chemokine receptor type 9; IL: Interleukin; PROs: Patient-reported outcomes; Vh:Cd: Villous height to crypt depth ratio.