Beyond gluten-free diet: Novel therapeutic frontiers in celiac disease armamentarium

Table 1 Emerging biomarkers in celiac disease

Biomarker	Biological basis	Clinical application	Diagnostic performance	Ref.
Faecal/urinary GIP	Partially digested gluten fragments in urine/faeces	Objective assessment of GFD adherence; detects recent gluten ingestion	No fixed sensitivity/specificity for gluten exposure (depends on timing of collection; short detection window (24-48 hours)	[41-45]
			Repeated GIP testing correlates with mucosal status but does not independently predict healing
tTG-neo antibodies	Antibodies to neo-epitopes formed by tTG-gliadin complexes	Diagnosis of active CeD	Sensitivity 98%-100%, specificity 93%-96% [vs anti tTG antibodies (sensitivity 74%-100%, specificity 78%-100%)]	[46-48,58]
			Accuracy for detecting villous atrophy in GFD patients: 90%, higher than other serologic tests
HLA DQ2 gliadin tetramer assay	Identifies circulating gluten-specific CD4+ T cells	Diagnosis of CeD even if patients are on GFD	On GFD, sensitivity 97%, specificity 95%	[51]
			On gluten diet, sensitivity 100%, specificity 90%
Serum IL-2 rise post gluten challenge	Rapid cytokine surge reflecting acute gluten-specific T-cell activation	Detects acute gluten exposure	No validated sensitivity/specificity reported yet; consistent IL-2 peak at about 4 hours after gluten ingestion	[52-54]
Circulating microRNAs	Altered expression patterns reflect mucosal injury	Exploratory diagnostic biomarker	No validated sensitivity/specificity	[56,57]

CeD: Celiac disease; GFD: Gluten-free diet; GIP: Gluten immunogenic peptides; tTG: Tissue transglutaminase inhibitor; IL: Interleukin; HLA-DQ2: Human leucocyte antigen-DQ2.

Table 2 Summary of key published trials on celiac disease drugs

Drug	Mechanism	Trial design	Result	Ref.
AN-PEP	Gastric active enzyme; degrades gluten peptides	RCT in a complex meal setting (containing 0.5 g gluten); measured gastric/duodenal gluten levels	Significantly degraded most gluten in stomach	[145]
AN-PEP	Oral glutenase	RCT, CeD on GFD; 650 mg × 3/day × 4 weeks	No significant reduction in stool GIP vs placebo	[68]
Latiglutenase (ALV003/IMGX003)	Combination oral glutenase	Phase 2 RCT (multicentre); 494 symptomatic CeD; multiple doses tested (100-900 mg); 12-24 weeks	No overall improvement in histology or symptoms vs placebo	[71]
			Post-hoc analysis showed symptom benefit in seropositive subgroup
Latiglutenase (ALV003/IMGX003)	Combination oral glutenase	Phase 2 gluten challenge RCT; 1200 mg latiglutenase; 2 g/day gluten × 6 weeks	Reduced mucosal damage and symptom severity vs placebo	[146]
TAK 062 (kuma 062/zamaglutenase	Engineered protease, active at gastric pH	RCT phase 2 (ILLUMINATE-062 trial) (NCT05353985) in 153 CeD patients, used SIGE-gluten bar	Well tolerated; no significant benefit over placebo	[75]
BL 7010	Non-absorbable gluten sequestering polymer	Phase 1/2 RCT; well-controlled CeD; single and repeated doses	Safe, limited systemic absorption; full results unpublished	[79]
Larazotide acetate (AT 1001)	Zonulin pathway blocker, stabilizes tight junctions	Meta-analysis of 4 RCTs	Well tolerated; improved GI symptoms vs placebo	[83]
Larazotide acetate	Zonulin pathway blocker, stabilizes tight junctions	Phase 3 RCT (CedLara)	Terminated due to sample size	[84]
ZED 1227	Oral selective intestinal tTG2 inhibitor	Phase 2 gluten challenge RCT; 6 weeks ZED 1227 at 3 different doses	Dose dependent mucosal protection; improved symptoms	[86]
Budesonide	Locally acting steroid; reduced systemic absorption	RCT, 20 CeD patients with malabsorption, budesonide 6 mg × 4 weeks plus GFD	Greater efficacy in relieving symptoms vs GFD alone	[95]
AMG 714 (PRV 015)	Anti-IL15 mAb (blocks IL15)	Phase 2a gluten challenge RCT; AMG 150 mg or 300 mg given as 2 subcutaneous injections every 2 weeks × 10 weeks	Failed primary endpoint (Vh:Cd) change (baseline and week 12) but improved symptoms and IEL density	[105]
AMG 714	Anti-IL15 mAb	Phase 2a RCT; 28 patients [refractory CeD type II; 2 IV doses of AMG 714 (8 mg/kg)] over 10 weeks vs placebo	No change in aberrant IELs but symptomatic benefit	[106]
CALY 002 (PRV-015)	Anti-IL15 mAb	Phase 1 a/b gluten challenge RCT	Good tolerability; attenuated mucosal injury	[107]
Anti-α4β7 integrin (vedolizumab)	Blocks gut-homing lymphocytes	Phase 2 gluten challenge RCT	Terminated due to insufficient enrollment	[104]
Tofacitinib	Small molecule JAK 1/3 inhibitor	Open label study; refractory type II CeD; 6 patients	Clinical and histologic benefit, but no change in the amount of aberrant IELs	[111]
Teriflunomide	Lymphocyte proliferation inhibitor (suppresses de novo pyrimidine synthesis)	Gluten challenge phase 2a RCT; 15 CeD patients; assessed gluten specific T cell activation and efflux using HLA DQ gluten tetramers	Teriflunomide was not effective in reducing gluten specific T cell activity vs placebo	[113]
RO5459072 (cathepsin S inhibitor)	Antigen presentation blocker	Single centre, gluten challenge RCT; 19 CeD patients; 100 mg × 2/day	Primary endpoint (↑ gliadin-specific IFN-γ secreting T cells) not met	[117]
NexVax2	Peptide vaccine (3 synthetic gliadin peptides	Phase 2 RCT; multicentre	Stopped early (no benefit)	[120]
KAN 101	Liver targeted glycopolymer gluten conjugate	Phase 1 RCT; HLA DQ2.5 CeD	Safe; rapid clearance	[122-124]
		ACeD-it phase 1b/2 RCT	Reduced T-cell/cytokine activation, improved PROs
		SynCeD phase 2a trial ongoing
TAK 101	Gliadin coated nanoparticles (IV, liver targeting)	Phase 1/2 gluten challenge RCT; 33 patients	Well tolerated; prevented mucosal injury	[125]
		Phase 2a RCT; 33 CeD, 14 day gluten challenge	↓ Gluten-specific IFN-γ+ T cells, mucosal protection vs placebo
TPM502	Nanoparticles carrying 3 gluten peptides	Phase 2a RCT	Safe; induced tolerance, ↓ IL-2/IFN-γ release, improved symptoms	[127,128]
Necator americanus (hookworm)	Immune deviation	RCT phase 1; 54 CeD; escalating gluten consumption	Improved symptoms at low gluten exposure; no sustained tolerance	[131]
Oligofructose enriched inulin	Prebiotic	RCT; 34 paediatric CeD; 12 weeks supplementation of oligofructose enriched inulin (10 g/day)	In patients with increased intestinal permeability, supplementation improved calprotectin and SAT	[147]
Oligofructose enriched inulin (synergy 1)	Prebiotic	34 paediatric CeD given synergy 1 (10 g/day) vs placebo (maltodextrin 7 g/day)	Synergy 1 modestly altered fecal microbiota quality and increased bacterial metabolite production	[148]
Probiotics (Bifidobacterium, VSL3)	Modulate microbiota; prevent barrier dysfunction	Small RCTs	Some symptom benefit; inconsistent mucosal/serology effect	[137,139]
IMV 856 (SIRT 6 modulator)	Enhances epithelial regeneration	Phase 1 RCT; 10-160 mg	Safe, less villous height reduction	[142]
MSCs	Immunomodulatory, regenerative	Case reports in RCD II	Symptomatic benefit; experimental	[141]

AN-PEP: Aspergillus niger prolyl-endopeptidase; CeD: Celiac disease; GFD: Gluten-free diet; RCT: Randomized controlled trial; SIGE: Simulated inadvertent gluten exposure; tTG: Tissue transglutaminase inhibitor; RCD: Refractory celiac disease; HLA: Human leucocyte antigen; IL: Interleukin; IFN: Interferon: Vh:Cd: Villous height-to-crypt depth; GIP: Gluten immunogenic peptide; IELs: Intraepithelial lymphocytes; JAK: Janus kinase; SAT: Sugar absorption test.