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Larazotide Acetate

Tier 1 · Human trials
Also known as AT-1001 · INN-202 · Larazotide

The strongest evidence is Tier 1: multiple randomized, double-blind, placebo-controlled human trials in adults with celiac disease (including a 342-patient multicenter trial, a 184-patient gluten-challenge study, an 86-patient study, a phase 3 trial NCT03569007), plus meta-analyses and pooled analyses. Mechanistic detail comes from in vitro (Caco-2, MDCK) and expert-opinion reviews; uses beyond celiac disease (arthritis, colitis, aortic aneurysm) rest on Tier 2 animal/in vitro models only. Vendor (Tier 3) claims about injectable dosing and non-celiac uses conflict with the clinical literature. One important caveat: the phase 3 trial (NCT03569007) does not actually contribute efficacy evidence. Its ClinicalTrials.gov record shows the study was terminated by the sponsor (9 Meters Biopharma) before completion (completion date July 2022), so no phase 3 efficacy readout is available. Descriptions of larazotide as 'currently being studied in phase III' predate this termination.

Half-life
Not recorded
Routes
Oral (all clinical trials; locally acting, non-systemic) · Subcutaneous injection (described only by a Tier-3 vendor website, not supported by clinical literature)
Goals
Gut barrier / intestinal health · Celiac disease symptom management (adjunct to gluten-free diet) · Anti-inflammatory (investigational, animal models)
Cost / mg
Not recorded

How it works

Multiple sources describe larazotide acetate (also called AT-1001 and INN-202) as a small, 8-amino-acid oral peptide that acts locally in the gut without being absorbed into the bloodstream. Reviews explain that in celiac disease, gluten triggers the release of a protein called zonulin, which loosens the 'tight junctions' between the cells lining the intestine, letting gluten fragments slip through and provoke an immune reaction. Reviews report that larazotide is thought to work as a zonulin antagonist — helping the tight junctions close and reassemble, so the gut barrier stays intact and gluten is kept from reaching the tissue underneath where it would spark inflammation.

Overview

Overview

Multiple sources describe larazotide acetate (also called AT-1001 and INN-202) as a novel, locally acting, non-systemic, synthetic single-chain oral peptide of 8 amino acids that acts as a tight junction regulator to restore intestinal barrier function. The DrugBank database lists it as an octapeptide inhibitor of paracellular permeability (chemical formula C32H55N9O10, average molecular weight 725.845, monoisotopic weight 725.407189007), classified as a small molecule with investigational status, whose structure is derived from the zonula occludens toxin (Zot) secreted by Vibrio cholerae. A review adds that it is also derived from human zonulin, a modulator of tight junction permeability with elevated intestinal tissue expression in celiac patients.

Rationale in Celiac Disease

Sources report that celiac disease affects roughly 1% of the western population (global prevalence cited as 0.7–1.4%), corresponding to about 3 million people in the United States, with a cited diagnosis rate of 15%. Human observational reports state that recurrent celiac signs and symptoms from inadvertent or deliberate gluten exposure have been reported in approximately 70% of celiac patients on a gluten-free diet. Reviews describe larazotide acetate as a first-in-class tight junction regulator being developed as an adjunct/adjuvant to a gluten-free diet, addressing what those reviews characterize as an unmet need in that, they note, the diet alone is difficult and costly and does not fully control symptoms or prevent mucosal damage. A study describes the underlying pathway in which gliadin indirectly stimulates zonulin secretion, which opens tight junctions and delivers gliadin peptides to the lamina propria; human observational reports state this increased paracellular permeability promotes gluten transport to gut-associated lymphoid tissue, initiating inflammatory cytokine release and T-cell recruitment.

Human Clinical Evidence

Reviews report that larazotide acetate reached phase II and phase III trials, orally administered to adult celiac patients; the phase 3 trial (NCT03569007) was later terminated by the sponsor before completion. Key findings from the provided sources:

  • A multicenter randomized, double-blind, placebo-controlled trial of 342 adults on a gluten-free diet for ≥12 months (4-week placebo run-in, 12-week treatment, 4-week placebo run-out) reported that larazotide acetate 0.5 mg three times daily met the primary endpoint with fewer symptoms than placebo (ANCOVA p=0.022, MMRM p=0.005), while the 1 mg and 2 mg doses were no different from placebo for any endpoint. The 0.5 mg dose produced a 26% decrease in Celiac Disease PRO Symptomatic Days (p=0.017), a 31% increase in Improved Symptom Days (p=0.034), a ≥50% reduction in weekly average Abdominal Pain Score for ≥6 of 12 weeks (p=0.022), and a decrease in headache and tiredness (p=0.010).
  • A randomized, double-blind study of 184 patients given larazotide acetate 1, 4, or 8 mg three times daily or placebo while receiving 2.7 g gluten daily for 6 weeks reported that the 1 mg dose limited gluten-induced symptoms by GSRS (P=0.002 vs placebo). Mean ratios of anti-tissue transglutaminase IgA over baseline were 19.0 (placebo) versus 5.78 (1 mg, P=0.010), 3.88 (4 mg, P=0.005), and 7.72 (8 mg, P=0.025); no significant differences in lactulose-to-mannitol (LAMA) ratios were observed.
  • A randomized, double-blind study of 86 patients (0.25, 1, 4, or 8 mg three times daily over 14 days with a 2.4 g/day gluten challenge) reported that larazotide appeared to limit gluten-induced worsening of GI symptom severity at some lower doses but not at the higher dose; LAMA measurements were highly variable in the outpatient setting.
  • Early gluten-challenge trials reported that larazotide prevented gluten-induced symptoms and blunted increases in anti-tissue transglutaminase antibodies, interferon-γ, and intestinal permeability.
  • A phase 3 trial (NCT03569007), actual enrollment 307, evaluated larazotide as enteric-coated beads in gelatin capsules dosed at 0.25 mg or 0.50 mg three times daily versus placebo, with the primary outcome being the proportion of binary responders with reduced CeD PRO Abdominal Domain scores at 12 weeks. Importantly, this study was terminated by the sponsor (9 Meters Biopharma) and did not run to completion — the ClinicalTrials.gov record lists its status as terminated (completion date July 2022). Reviews that describe larazotide as 'currently being studied in phase III' predate this termination, so that phrasing overstates the current development status; no positive phase 3 efficacy result is available in the sources here.

Meta-Analyses and Contested Findings

A meta-analysis of four RCTs comprising 626 patients (larazotide n=465, placebo n=161) — one source of which is a medRxiv preprint, with a corresponding peer-reviewed version — reported no significant difference between larazotide and placebo for change in the lactulose-to-mannitol ratio regardless of gluten status, but significantly better symptomatic improvement than placebo in the gluten-challenge subgroup (total GSRS and CD-specific GSRS) and not in the gluten-free subgroup. A pooled analysis of 3 studies (N=136) similarly reported change in urinary LAMA of 1.34 (95% CI 0.96–1.71) for larazotide versus 1.91 (95% CI 1.50–2.32) for placebo, and change in GSRS of 0.04 (95% CI −0.32 to 0.40) versus 0.46 (95% CI 0.09–0.83), concluding lower doses seemed to control gluten-challenge-induced symptoms.

These findings carry two important caveats. First, benefit appears setting-dependent: symptoms improved during gluten challenge but the meta-analyses found no significant benefit on a gluten-free diet alone, which contrasts with the single 342-patient trial that reported the 0.5 mg dose met its endpoint in gluten-free-diet patients. Second, efficacy shows an unusual inverse dose relationship — the 0.5 mg dose worked while 1 mg and 2 mg did not, and gluten-challenge studies found lower doses more effective; one review explicitly states clinical outcomes for larazotide are inconsistent.

Evidence Beyond Celiac Disease (Preclinical Only)

A review of 209 publications suggests larazotide, as a zonulin antagonist, could theoretically be a viable strategy for celiac disease, type 1 diabetes, autoimmune diseases, inflammatory bowel disease, Kawasaki disease, and respiratory diseases, but the review's extrapolation beyond celiac disease rests on animal and in vitro models with no supporting human clinical evidence. Nonclinical studies report proof-of-concept tight junction regulation, including inhibition of gliadin-induced tight junction alteration, macrophage recruitment, and increased permeability. Rodent and porcine studies extend this to collagen-induced arthritis in mice (where a study reports it reduced arthritis onset), intestinal ischemic injury in pigs, DSS-induced colitis in mice (where a study reports sustained-release larazotide reduced disease activity, suppressed pro-inflammatory cytokines while upregulating IL-10, repaired tight junctions ZO-1/occludin/claudin-5, restored MUC2 mucus production, and rebalanced gut microbiota), and a BAPN-induced thoracic aortic aneurysm/dissection mouse model (where AT-1001, described there as a protease-activated receptor 2 inhibitor, sealed tight junctions, reduced TAAD incidence, and attenuated vascular inflammation and edema). All of these applications rest on animal and in vitro models, not human trials.

For context, a review notes that among alternatives to the gluten-free diet, double-blind placebo-controlled trials of an oral recombinant glutenase (ALV003) showed significant but limited benefit in gluten-free-diet-compliant celiac patients, while other approaches targeting other immune mechanisms have not been as positive.

Vendor and Community Claims (Tier 3 — Not Supported by Clinical Literature)

A Tier-3 vendor website describes larazotide as a tight-junction regulator studied for gut barrier and celiac-associated symptoms, and further claims it demonstrated accelerated wound healing and soft tissue repair, beneficial effects on the intestinal lining and GI function, reduced joint inflammation with improved mobility, and possible support for faster recovery from muscle strains and exercise stress. The same vendor reports that among 6 community users, recovery was the most reported benefit and digestive upset the most reported side effect, with a median reported community dose of 1000–2000 mcg and 100% neutral sentiment (0% positive, 0% negative), alongside a suggested timeline of initial anti-inflammatory effects at weeks 1–2, improved tissue mobility at weeks 2–4, recovery milestones at weeks 4–8, and near-complete healing at weeks 8–12. These claims, and the injectable route and non-celiac uses they describe, are not supported by the clinical literature, which uniformly describes larazotide as a locally acting, non-systemic oral peptide for celiac disease. Separately, one Tier-3 review mischaracterizes larazotide as 'a monoclonal antibody,' conflicting with all other sources and with DrugBank's small-molecule/8-amino-acid peptide classification.

What the research shows

197 findings extracted from the 29 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 52 human trial findings, 1 human study finding, 7 animal findings, 1 in vitro finding, 8 expert opinion findings and 1 anecdotal finding.

  • human trialLarazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity at some lower doses but not at the higher dose1

  • human trialChange in urinary lactulose to mannitol fractional excretion ratio (LAMA) scores from baseline after the intervention in LA group was 1.34 (95% CI=0.96 to 1.71)2

  • human trialChange in urinary lactulose to mannitol fractional excretion ratio (LAMA) scores from baseline in placebo group was 1.91 (95% CI=1.50 to 2.32)2

  • human trialChange in Gastrointestinal Symptom Rating scale (GSRS) scores after intervention was 0.04 (95% CI=-0.32 to 0.40) in LA group2

  • human trialChange in Gastrointestinal Symptom Rating scale (GSRS) scores after intervention was 0.46 (95% CI=0.09 to 0.83) in placebo group2

  • human trialChange in Celiac disease GSRS (CeD-GSRS) scores after intervention was -0.11 (95% CI=-0.48 to 0.26) in LA group2

  • human trialChange in Celiac disease GSRS (CeD-GSRS) scores after intervention was 0.35 (95% CI=-0.29 to 0.99) in placebo group2

  • human trialLower doses of Larazotide acetate seemed to control gastrointestinal symptom severity induced by the gluten challenge in celiac patients2

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  • human trialLarazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone3

  • human trialThe primary endpoint was met at the 0.5 mg dose of larazotide acetate with fewer symptoms compared with placebo (ANCOVA p=0.022, MMRM p=0.005)3

  • human trialThe 0.5mg dose showed 26% decrease in Celiac Disease Patient Reported Outcome Symptomatic Days (p=0.017)3

  • human trialThe 0.5mg dose showed 31% increase in Improved Symptom Days (p=0.034)3

  • human trialThe 0.5mg dose showed ≥50% reduction from baseline of weekly average Abdominal Pain Score for ≥6 out of 12 weeks of treatment (p=0.022)3

  • human trialThe 0.5mg dose showed a decrease in Non-GI symptoms of headache and tiredness (p=0.010)3

  • human trialThe 1 and 2 mg doses were no different than placebo for any endpoint3

  • human trialStudy included 342 adults in a multicenter randomized, double-blind, placebo-controlled design3

  • human trialLarazotide acetate 0.5 mg three times daily met the primary endpoint with fewer symptoms compared with placebo (ANCOVA p=0.022, MMRM p=0.005)4

  • human trialThe 0.5 mg dose showed 26% decrease in Celiac Disease Patient Reported Outcome Symptomatic Days (p=0.017)4

  • human trialThe 0.5 mg dose showed 31% increase in Improved Symptom Days (p=0.034)4

  • human trialThe 0.5 mg dose showed ≥50% reduction from baseline of weekly average Abdominal Pain Score for ≥6 out of 12 weeks of treatment (p=0.022)4

  • human trialThe 0.5 mg dose showed a decrease in Non-GI symptoms of headache and tiredness (p=0.010)4

  • human trialLarazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo)5

  • human trialMean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010) in the larazotide acetate 1-mg group5

  • human trialMean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 3.88 (P = 0.005) in the larazotide acetate 4-mg group5

  • human trialMean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 7.72 (P = 0.025) in the larazotide acetate 8-mg group5

  • human trialNo significant differences in LAMA ratios were observed between larazotide acetate and placebo groups5

  • human trialLA is currently being studied in phase III clinical trials and is orally administered to adult patients with celiac disease as an adjunct therapeutic to enhance intestinal barrier function7

  • human trialStudy evaluated efficacy and safety of larazotide acetate versus placebo for relief of persistent symptoms in adult celiac disease patients on a gluten-free diet9

  • human trialPrimary outcome was proportion of subjects who are binary responders with reduction in CeD PRO Abdominal Domain scores at 12 weeks9

  • human trialFour RCTs met eligibility criteria, comprising 626 patients (AT-1001, n=465, placebo, n=161)11

  • human trialFor change in lactulose-to-mannitol ratio, the endpoint did not significantly differ between AT-1001 and placebo groups, irrespective of the gluten status11

  • human trialAT-1001 treatment (compared with placebo) significantly correlated with better symptomatic improvement in the two endpoints of change in total gastrointestinal symptom rating scale (total GSRS) and CD-specific GSRS in patients undergoing gluten challenge11

  • human trialNo significant difference was noted among patients undergoing GFD for total GSRS and CD-GSRS endpoints11

  • human trialLA is currently being studied in phase III clinical trials12

  • human trialFour RCTs met eligibility criteria, comprising 626 patients (larazotide acetate, n = 465, placebo, n = 161)13

  • human trialFor change in lactulose-to-mannitol ratio, the overall effect estimate did not reveal a significant difference between larazotide acetate and placebo groups13

  • human trialLarazotide acetate significantly yielded better symptomatic improvement in the gluten challenge but not gluten free subgroup for change in total gastrointestinal symptom rating scale (GSRS)13

  • human trialSimilar finding was found for change in celiac-disease GSRS (CD-GSRS) favoring the gluten challenge over gluten free subgroup13

  • human trialLarazotide acetate favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge compared to placebo13

  • human trialLarazotide acetate is well-tolerated and superior to placebo in alleviating gastrointestinal symptoms13

  • human trialTreatment with larazotide acetate effectively reduces arthritis onset14

  • human trialLarazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone16

  • human trialThe 0.5-mg dose showed a 26% decrease in celiac disease patient-reported outcome symptomatic days16

  • human trialThe 0.5-mg dose showed a 31% increase in improved symptom days16

  • human trialThe 0.5-mg dose showed a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment16

  • human trialThe 0.5-mg dose showed a decrease in the nongastrointestinal symptoms of headache and tiredness16

  • human trialIn initial clinical trials using gluten challenge, larazotide acetate prevented gluten-induced symptoms and blunted increases in anti-tissue transglutaminase antibodies, interferon-γ, and intestinal permeability16

  • human trialLarazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS17

  • human trialNo significant differences in LAMA ratios were observed between larazotide acetate and placebo groups17

  • human trialMean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 in the larazotide acetate 1-mg group17

  • human trialMean ratio of anti-tissue transglutaminase IgA levels was 3.88 in the larazotide acetate 4-mg group17

  • human trialMean ratio of anti-tissue transglutaminase IgA levels was 7.72 in the larazotide acetate 8-mg group17

  • human studyRecurrent celiac disease signs and symptoms due to inadvertent or deliberate gluten exposure have been reported in approximately 70% of celiac disease patients on a gluten-free diet4

  • animalSmall (rodent) and large (porcine) animal studies have been conducted that demonstrate the importance of LA as a tight junction regulatory peptide in conditions other than celiac disease, including collagen-induced arthritis in mice and intestinal ischemic injury in pigs.6

  • animalSmall (rodent) and large (porcine) animal studies have been conducted that demonstrate the importance of LA as a tight junction regulatory peptide in conditions other than celiac disease, including collagen-induced arthritis in mice and intestinal ischemic injury in pigs7

  • animalSmall (rodent) animal studies have been conducted that demonstrate the importance of LA as a tight junction regulatory peptide in collagen-induced arthritis in mice12

  • animalLarge (porcine) animal studies have been conducted that demonstrate the importance of LA as a tight junction regulatory peptide in intestinal ischemic injury in pigs12

  • animalIn DSS-induced colitis mice, sustained-release larazotide acetate significantly reduced disease activity19

  • animalAT-1001 alleviated BAPN-induced impairment of endothelial tight junction function and expression20

  • animalAT-1001 reduced TAAD incidence in BAPN-induced mouse model20

  • in vitroLarazotide acetate restores epithelial integrity in LPS-injured Caco-2 cells19

  • expert opinionZonulin antagonists like larazotide acetate have reached phase II/III clinical trials15

  • expert opinionDemonstrated acceleration of wound healing and soft tissue repair in research24

  • expert opinionResearch shows beneficial effects on intestinal lining and GI function24

  • expert opinionAssociated with reduced joint inflammation and improved mobility24

  • expert opinionLarazotide acetate, as a monoclonal antibody targeting immune pathways, requires further validation in pediatric populations26

  • expert opinionA gluten-free diet alone is not sufficient to control symptoms and prevent mucosal damage from unintentional gluten exposure27

  • expert opinionMost recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet29

  • expert opinionOther studies have addressed other immune mechanisms that may play a role in celiac disease pathogenesis and have not been so positive29

  • anecdotal6 community users report recovery as most reported benefit24

How it works

Based on 13 human trial findings, 6 human study findings, 13 animal findings, 8 in vitro findings, 19 expert opinion findings and 5 theoretical findings.

  • human trialLarazotide acetate is a novel, locally acting non-systemic, synthetic 8-amino acid oral peptide3

  • human trialLarazotide acetate appears to prevent opening of intestinal tight junctions by promoting tight junction assembly and actin filament rearrangement, which prevents gluten from reaching the intestinal submucosa and triggering an inflammatory response4

  • human trialLarazotide acetate (LA) is a single-chain peptide of eight amino acids that acts as a tight junction regulator to restore intestinal barrier function.6

  • human trialLA is thought to act as a zonulin antagonist to reduce zonulin-induced increases in barrier permeability.6

  • human trialLA has been associated with the redistribution and rearrangement of tight junction proteins and actin filaments to restore intestinal barrier function.6

  • human trialLA has been linked to inhibition of myosin light chain kinase, which likely reduces tension on actin filaments, thereby facilitating tight junction closure.6

  • human trialLarazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of CD11

  • human trialLA has been associated with the redistribution and rearrangement of tight junction proteins and actin filaments to restore intestinal barrier function12

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  • human trialLarazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of celiac disease13

  • human trialThe paracellular pathway encompasses the delivery of gliadin peptides to lamina propria through disassembling of tight junctions known as zonula occludens, mediated by zonulin13

  • human trialLarazotide acetate is a zonulin antagonist that specifically increases intestinal barrier integrity14

  • human trialLarazotide acetate is a novel, locally acting, nonsystemic, synthetic, 8–amino acid oral peptide16

  • human trialLarazotide acetate appears to prevent opening of intestinal tight junctions by promoting tight junction assembly and actin filament rearrangement, which prevents gluten from reaching the intestinal submucosa and triggering an inflammatory response16

  • human studyIn patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine1

  • human studyTight junction disassembly and paracellular permeability have an important role in the transport of gluten peptides to the lamina propria1

  • human studyIn CeD, paracellular permeability is increased by an inflammatory response to gluten entry into the intestinal mucosa3

  • human studyIn celiac disease, paracellular permeability is increased by an inflammatory response to gluten entry into the intestinal mucosa4

  • human studyIncreased permeability promotes gluten peptide transport to gut-associated lymphoid tissue, initiating inflammatory cytokine release and T-cell recruitment4

  • human studyAberrant endothelial tight junction expressions were found in thoracic aortas of patients with TAAD by single-cell RNA sequencing analysis20

  • animalNonclinical studies with larazotide acetate have demonstrated proof-of-concept of tight junction regulation including the inhibition of gliadin-induced tight junction alteration, macrophage recruitment and increases in intestinal permeability4

  • animalNonclinical studies with larazotide acetate have shown proof-of-concept of tight junction regulation including the inhibition of gliadin-induced tight junction alteration, macrophage recruitment, and increases in intestinal permeability16

  • animalLarazotide acetate suppressed pro-inflammatory cytokines and upregulated anti-inflammatory IL-10 in DSS-induced colitis mice19

  • animalLarazotide acetate repaired tight junctions (ZO-1, occludin and claudin-5) in DSS-induced colitis mice19

  • animalLarazotide acetate restored mucus production (MUC2) in DSS-induced colitis mice19

  • animalLarazotide acetate rebalanced gut microbiota in DSS-induced colitis mice19

  • animalIn a BAPN-induced TAAD mouse model, endothelial tight junction function was disrupted in thoracic aortas at early stage (5 and 10 days)20

  • animalIntercellular distribution of crucial tight junction components was significantly decreased in BAPN-induced TAAD mouse model by en face staining20

  • animalAT-1001 (protease-activated receptor 2 inhibitor) seals tight junctions20

  • animalAT-1001 attenuated vascular inflammation and edema in thoracic aortas of BAPN-fed mice20

  • animalEndothelial-targeted ZO-1 conditional knockout increased TAAD incidence20

  • animalDisruption of endothelial tight junction function is an early event prior to TAAD formation20

  • animalA substantial role of zonulin in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro21

  • in vitroLarazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions1

  • in vitroLarazotide acetate selectively inhibits zonulin-mediated tight junction disruption via combating MLCK/p-MLC signals19

  • in vitroLarazotide acetate is an 8-mer peptide and TJ modulator23

  • in vitroLarazotide acetate inhibits TJ disassembly and dysfunction caused by endogenous and exogenous stimuli in intestinal epithelial cells23

  • in vitroLarazotide acetate promoted TJ assembly in a calcium switch assay in MDCK cells23

  • in vitroLarazotide acetate promoted actin rearrangement and junctional distribution of zonula occludens-1 (ZO-1), occludin, claudins, and E-cadherin23

  • in vitroLarazotide acetate promoted TJ maturation and decreased paracellular permeability in Caco-2 cells23

  • in vitroLarazotide acetate enhances TJ assembly and barrier function by promoting actin rearrangement and redistribution of TJ and AJ proteins23

  • expert opinionCeliac disease pathogenesis involves increased permeability of intestinal epithelial tight junctions due to immunogenic mechanisms2

  • expert opinionLarazotide acetate is a tight junction regulator peptide2

  • expert opinionLarazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae5

  • expert opinionLarazotide acetate is a single-chain peptide of eight amino acids that acts as a tight junction regulator to restore intestinal barrier function7

  • expert opinionMechanistically, LA is thought to act as a zonulin antagonist to reduce zonulin-induced increases in barrier permeability7

  • expert opinionLA has been associated with the redistribution and rearrangement of tight junction proteins and actin filaments to restore intestinal barrier function7

  • expert opinionLA has been linked to inhibition of myosin light chain kinase, which likely reduces tension on actin filaments, thereby facilitating tight junction closure7

  • expert opinionLA is derived from human zonulin, a known modulator of tight junction permeability that has elevated intestinal tissue expression in patients with celiac disease7

  • expert opinionLA shares structural similarities to the Vibrio cholerae zonula occludens toxin (Zot), which is an enterotoxin that disrupts intercellular tight junction structure through actin polymerization and cytoskeletal modifications7

  • expert opinionAn octapeptide inhibitor of paracellular permeability whose structure is derived from a protein (zonula occludens toxin) secreted by Vibrio cholerae for treatment of Coeliac disease8

  • expert opinionLarazotide acetate is a zonulin antagonist used to prevent uptake of digested gluten through intestinal epithelial tight junctions15

  • expert opinionLarazotide acetate is a first-in-class oral peptide that prevents tight junction opening17

  • expert opinionLarazotide acetate is a first in class oral peptide developed as a tight junction regulator18

  • expert opinionGliadin indirectly stimulates the secretion of zonulin from the lamina propria of the intestine into the intestinal lumen, which leads to binding of zonulin to apical receptors of the enterocyte, initiating tight junction events18

  • expert opinionNew possible molecular targets for Larazotide have been demonstrated21

  • expert opinionCurrent approaches in development for celiac disease treatment target barrier function, immune responses, detoxifying gluten or sequestering gluten22

  • expert opinionIncreased intestinal permeability is a central component to the pathophysiology of coeliac disease25

  • expert opinionCeliac Disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals27

  • expert opinionLarazotide acetate represents one of several potential therapeutic targets in the immune-mediated cascade of celiac disease28

  • theoreticalLarazotide acetate is a single-chain peptide of eight amino acids that acts as a tight junction regulator to restore intestinal barrier function12

  • theoreticalLA is thought to act as a zonulin antagonist to reduce zonulin-induced increases in barrier permeability12

  • theoreticalLA has been linked to inhibition of myosin light chain kinase, which likely reduces tension on actin filaments, thereby facilitating tight junction closure12

  • theoreticalZonulin modulates the competency of intercellular tight junctions with a subsequent increase in epithelial and endothelial permeability21

  • theoreticalLarazotide is a zonulin antagonist21

Dosing

Based on 4 human trial findings and 2 expert opinion findings.

  • human trialThe 1 and 2 mg doses were no different than placebo for any endpoint4

  • human trialPatients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks5

  • human trialLarazotide acetate was dosed at 0.25 mg TID or 0.50 mg TID9

  • human trialThe 1- and 2-mg doses were no different than placebo for any end point16

  • expert opinionStarting dose 100 mcg once daily subcutaneous injection24

  • expert opinionStandard dose 250 mcg once daily subcutaneous injection24

How the body handles it

Based on 2 human trial findings, 3 animal findings and 1 in vitro finding.

  • human trialLAMA measurements were highly variable in the outpatient setting1

  • human trialThe increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control1

  • animalOral dosing of larazotide acetate (1 mg total) in overnight fasted pigs resulted in time dependent appearance of larazotide acetate in the distal duodenum and proximal jejunum18

  • animalPeak larazotide acetate concentrations occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing18

  • animalLarazotide acetate is available in detectable concentrations at the site of celiac disease18

  • in vitroA delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of celiac disease18

Safety and side effects

Based on 14 human trial findings, 2 expert opinion findings and 4 anecdotal findings.

  • human trialLarazotide acetate was generally well tolerated with no serious adverse events observed1

  • human trialThe most common adverse events were headache and urinary tract infection1

  • human trialOdds ratio for overall adverse events (gastrointestinal symptoms, headache, urinary tract infection, fatigue) in LA group versus placebo group was 0.60 (95% CI=0.28 to 1.28)2

  • human trialLarazotide acetate has a relatively safe side effect profile compared to placebo2

  • human trialSafety was comparable to placebo3

  • human trialIn four prior clinical trials, larazotide acetate demonstrated a safety profile comparable to placebo4

  • human trialSafety was comparable to placebo for larazotide acetate4

  • human trialAdverse event rates were similar between larazotide acetate and placebo groups5

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  • human trialAT-1001 favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge compared with placebo11

  • human trialOther AEs were comparable between both AT-1001 and placebo groups11

  • human trialAT-1001 is largely well-tolerated11

  • human trialOther adverse events were comparable between both treatment groups13

  • human trialSafety was comparable with placebo16

  • human trialAdverse event rates were similar between larazotide acetate and placebo groups17

  • expert opinionGenerally well-tolerated in research settings24

  • expert opinionPotential effect on blood pressure (monitor if hypertensive)24

  • anecdotalMild nausea with higher doses24

  • anecdotalInjection site redness or discomfort24

  • anecdotalRare: Dizziness or lightheadedness24

  • anecdotal6 community users report digestive upset as most reported side effect24

What people use it for

Based on 6 human trial findings, 2 human study findings and 16 expert opinion findings.

  • human trialLarazotide acetate is a first-in-class tight junction (TJ) regulator under development as an adjunct to a GFD3

  • human trialStudy population was adults with CeD who had been on a GFD for ≥12 months3

  • human trialLarazotide acetate is a first-in-class tight junction regulator under development as an adjunct to a gluten-free diet4

  • human trialLA is currently being studied in phase III clinical trials and is orally administered to adult patients with celiac disease as an adjunct therapeutic to enhance intestinal barrier function that has been disrupted by gliadin-induced immune reactivity.6

  • human trialLA is orally administered to adult patients with celiac disease as an adjunct therapeutic to enhance intestinal barrier function that has been disrupted by gliadin-induced immune reactivity12

  • human trialLarazotide acetate can be used as a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function14

  • human studyCeliac disease affects approximately 1% of the western population3

  • human studyRecurrent celiac disease signs and symptoms due to inadvertent or deliberate gluten exposure have been reported in approximately 70% of CeD patients on a GFD3

Show the remaining 16

  • expert opinionGroup: Investigational8

  • expert opinionLarazotide acetate may reduce gluten uptake and associated sequelae17

  • expert opinionLarazotide acetate is a lead candidate for management of celiac disease18

  • expert opinionLarazotide could be employed as a viable therapeutic strategy for chronic and acute inflammatory diseases21

  • expert opinionLarazotide may be efficacious for treatment of celiac disease, type 1 diabetes, autoimmune diseases, inflammatory bowel disease, Kawasaki disease, and respiratory diseases21

  • expert opinionLarazotide acetate is an adjuvant therapy in development for celiac disease in conjunction with the gluten-free diet22

  • expert opinionTight-junction regulator peptide studied for gut barrier and celiac-associated symptoms24

  • expert opinionMay support faster recovery from muscle strains and exercise stress24

  • expert opinionLarazotide acetate is an experimental medication targeting barrier integrity and normalising intestinal permeability in coeliac disease25

  • expert opinionLarazotide acetate is a zonulin inhibitor showing promise for celiac disease treatment, though clinical outcomes are inconsistent26

  • expert opinionCurrently, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet27

  • expert opinionThere is an unmet need for non-dietary therapies for the management of CeD27

  • expert opinionLarazotide acetate is a modulator of enterocyte tight junctions being investigated as a non-dietary therapy for celiac disease28

  • expert opinionCeliac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals29

  • expert opinionCurrent treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly29

  • expert opinionAlternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet29

Other findings

Based on 2 human trial findings, 1 human study finding, 3 expert opinion findings and 1 theoretical finding.

  • human trialLarazotide acetate is a novel, locally acting non-systemic, synthetic 8-amino acid oral peptide4

  • human trialLarazotide acetate is a synthetic 8-amino acid peptide formulated as enteric-coated beads in gelatin capsules9

  • human studyCeliac disease affects approximately 1% of the western population4

  • expert opinionUse bacteriostatic water only. Avoid saline — may cause precipitation24

  • expert opinionRefrigerate and use within 28 days after reconstitution24

  • expert opinionCeD affects around 1% of the population worldwide27

  • theoreticalType: Small Molecule8

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

Larazotide's benefit depends on setting: symptoms improved during gluten challenge but not on a gluten-free diet alone in pooled analyses.

Meta-analyses of four RCTs (626 patients) and a pooled analysis (N=136) report significant symptomatic improvement (total GSRS, CD-GSRS) only in the gluten-challenge subgroup and no significant difference in the gluten-free subgroup, and no significant difference between larazotide and placebo for the lactulose-to-mannitol permeability ratio in any group. This contrasts with the single 342-patient trial reporting the 0.5 mg dose met its symptom endpoint in gluten-free-diet patients.

Single source

A vendor website describes uses, dosing and routes not supported by the clinical literature.

The tier-3 peptiq.io source describes subcutaneous injection dosing (100–250 mcg once daily) and uses such as wound healing, joint inflammation and muscle recovery, whereas all clinical trial sources describe larazotide as a locally acting, non-systemic ORAL peptide for celiac disease dosed in mg three times daily. The vendor's claims rest on expert opinion and only 6 anecdotal community reports.

Limited evidence

Uses beyond celiac disease rest on animal and in vitro models only.

Applications in arthritis, DSS-induced colitis, thoracic aortic aneurysm/dissection, and other inflammatory/autoimmune diseases are supported only by rodent, porcine, and in vitro studies, not human trials.

Limited evidence

Pharmacokinetic distribution data come from pigs and in vitro models.

Evidence that larazotide reaches its target site in detectable concentrations (0.32–1.76 μM peak in duodenum at 1 hour) is from an overnight-fasted pig study and an in vitro release model, not human PK data.

Preprint

One meta-analysis source is a preprint.

The 626-patient meta-analysis of four RCTs was posted on medRxiv (a preprint server); a corresponding peer-reviewed version appears as Larazotide acetate for treatment of celiac disease: A systematic review and meta-analysis of randomized controlled trials..

Safety and side effects

Safety and Tolerability

Human Trial Data (Tier 1)

The 342-patient multicenter trial reported that the safety of larazotide acetate was comparable to placebo, consistent with four prior clinical trials in which its safety profile was comparable to placebo. The 86-patient study reported larazotide was generally well tolerated with no serious adverse events, and that the most common adverse events were headache and urinary tract infection. In the 184-patient gluten-challenge study, adverse event rates were similar between larazotide and placebo groups.

A meta-analysis of four RCTs (626 patients) reported that larazotide favorably reduced the adverse event of gluten-related diarrhea in patients undergoing gluten challenge compared with placebo, with other adverse events comparable between groups, concluding it is well-tolerated and superior to placebo in alleviating GI symptoms. A pooled analysis (N=136) reported an odds ratio for overall adverse events (GI symptoms, headache, urinary tract infection, fatigue) of 0.60 (95% CI 0.28–1.28) for larazotide versus placebo, concluding a relatively safe side effect profile compared to placebo.

Vendor / Anecdotal Reports (Tier 3)

A vendor website reports larazotide is generally well-tolerated in research settings and lists anecdotal side effects of mild nausea at higher doses, injection site redness or discomfort, rare dizziness or lightheadedness, and a potential effect on blood pressure (advising monitoring if hypertensive). Among 6 community users cited by that vendor, digestive upset was the most reported side effect. These anecdotal reports pertain to a subcutaneous injection route that is not used in any clinical trial and should be weighed accordingly.

Caveats

The favorable safety picture comes from trials of an oral, locally acting, non-systemic formulation. Efficacy — and by extension the risk/benefit assessment — is contested: benefit was seen during gluten challenge but not clearly on a gluten-free diet alone in pooled analyses, and an unusual inverse dose relationship was observed (lower doses outperformed higher ones). Larazotide remains investigational and is not an approved therapy in the provided sources.

Reconstitution and handling

Dosing and Preparation

No dose has been established for this compound. Larazotide acetate is described across the sources as an investigational agent with no regulatory label, so the figures below are what specific sources report — not guidance.

Oral dosing used in clinical trials (Tier 1)

All clinical trials describe larazotide as a locally acting, non-systemic ORAL peptide, dosed in milligrams three times daily:

  • The 342-patient trial used 0.5 mg three times daily (the dose that met the primary endpoint); 1 mg and 2 mg three times daily did not differ from placebo.
  • The phase 3 trial (NCT03569007) used 0.25 mg or 0.50 mg three times daily, formulated as enteric-coated beads in gelatin capsules.
  • The 184-patient gluten-challenge study used 1, 4, or 8 mg three times daily (1 mg was effective).
  • The 86-patient study used 0.25, 1, 4, or 8 mg three times daily.

Across these Tier 1 celiac trials (the 342-patient trial and the gluten-challenge studies), an inverse dose relationship was reported: lower doses (0.25–1 mg) tended to outperform higher doses, as reported in the 342-patient trial (src-1) and the gluten-challenge studies (src-13, src-29). A pharmacokinetic in vitro study predicted a delayed-release formulation would release in the mid duodenum and jejunum, the target site of celiac disease. A porcine study reported that oral dosing of 1 mg total in overnight-fasted pigs produced detectable peptide concentrations at the celiac disease site (peak 0.32–1.76 μM in the duodenum at 1 hour; 0.02–0.47 μM distal duodenum and 0.00–0.43 μM proximal jejunum at 2–4 hours). This distribution evidence is from pigs and an in vitro model, not human PK.

Vendor-described injectable dosing (Tier 3 — not supported by clinical literature)

A single vendor website recommends a starting dose of 100 mcg once daily and a standard dose of 250 mcg once daily by subcutaneous injection, advises reconstitution with bacteriostatic water only (avoiding saline due to precipitation risk), and refrigeration (2–8°C) with use within 28 days after reconstitution. The same vendor reports a median community dose of 1000–2000 mcg among 6 users. These figures describe a subcutaneous route and microgram dosing that appear in no clinical trial — the trials use oral, milligram, three-times-daily dosing — and rest on expert opinion plus 6 anecdotal reports. The reconstitution instructions (bacteriostatic water, refrigeration, 28-day use window) are arithmetic and handling advice about an injectable preparation that is not the form studied clinically.

Note

Because larazotide's studied form is an oral, enteric-coated/delayed-release product designed to act locally in the small intestine, the concept of reconstituting a lyophilized vial with bacteriostatic water applies only to the vendor-described injectable presentation, not to the clinically studied oral formulations.

Sources

Ordered by evidence quality — the strongest first.

  1. A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten Challenge(opens in a new tab)
    Tier 1Web · journals.lww.com
  2. Journal of Gastroenterology, Pancreatology & Liver Disorders(opens in a new tab)
    Tier 1Web · symbiosisonlinepublishing.com
  3. Larazotide Acetate for Persistent Symptoms of Celiac Disease ... - PMC(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  4. Larazotide Acetate for Persistent Symptoms of Celiac Disease ... - PMC(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  5. Larazotide acetate in patients with coeliac disease undergoing a ...(opens in a new tab)
    Tier 1Web · celiacdiseasecenter.columbia.edu
  6. Larazotide acetate: a pharmacological peptide approach to tight junction ...(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  7. Larazotide acetate: a pharmacological peptide approach to tight junction ...(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  8. Larazotide: Uses, Interactions, Mechanism of Action | DrugBank Online(opens in a new tab)
    Tier 1Web · go.drugbank.com
  9. NCT03569007 | Study to Evaluate the Efficacy and Safety of Larazotide ...(opens in a new tab)
    Tier 1Web · clinicaltrials.gov
  10. Study Details | NCT00889473 | | ClinicalTrials.gov(opens in a new tab)
    Tier 1Web · clinicaltrials.gov
  11. Larazotide acetate for treatment of celiac disease: A systematic review and meta-analysis of randomized controlled trials.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  12. Larazotide acetate: a pharmacological peptide approach to tight junction regulation.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  13. Larazotide Acetate for Treatment of Celiac Disease: A Systematic ...(opens in a new tab)
    Tier 1Web · medrxiv.org · 2020
  14. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  15. Evolving Therapy for Celiac Disease.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2019
  16. Larazotide Acetate for Persistent Symptoms of Celiac Disease ...(opens in a new tab)
    Tier 1Web · gastrojournal.org · 2015
  17. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2013
  18. In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model(opens in a new tab)
    Tier 2Web · journals.plos.org
  19. Antibacterial hyaluronic acid hydrogel with sustained release of larazotide as effective colitis treatment.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  20. Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  21. The Therapeutic use of the Zonulin Inhibitor AT-1001 (Larazotide) for a Variety of Acute and Chronic Inflammatory Diseases.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  22. Pharmacological approaches in celiac disease.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2015
  23. Larazotide acetate promotes tight junction assembly in epithelial cells.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2012
  24. Larazotide — Dosing, Side Effects & Research - PeptIQ(opens in a new tab)
    Tier 3Web · peptiq.io
  25. Coeliac disease and the intestinal barrier: mechanisms of disruption and strategies for restoration.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  26. New Therapeutic Challenges in Pediatric Gastroenterology: A Narrative Review.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  27. Novel Nondietary Therapies for Celiac Disease.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2019
  28. Celiac disease 2015 update: new therapies.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2015
  29. Emerging drugs for celiac disease.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2015