Larazotide

Larazotide is an investigational eight-amino-acid peptide studied mainly as an oral treatment for persistent symptoms of celiac disease. Its acetate form, also called AT-1001, acts on the organization of the epithelial barrier in laboratory models. Clinical studies found symptom improvements in selected treatment groups, but permeability measurements were inconclusive or negative and the phase 3 celiac-disease program was discontinued. Its history is useful for understanding the distance between changing a cell-layer barrier and establishing a dependable patient benefit. A newer Long COVID trial has completed enrollment and follow-up, with no results posted in the registry checked for this review.

Overview

Larazotide acetate contains the peptide sequence Gly-Gly-Val-Leu-Val-Gln-Pro-Gly, abbreviated GGVLVQPG. The acetate salt is the form used in the cited celiac-disease clinical program. FDA records larazotide and larazotide acetate under separate substance identifiers, with AT-1001 listed as an alias of the acetate. These identity records help distinguish the material in a paper or product description. FDA larazotide identity, FDA larazotide acetate identity.

Molecular profile

Peptide sequence: GGVLVQPG (Gly-Gly-Val-Leu-Val-Gln-Pro-Gly) Source
Length: 8 amino-acid residues Source
Clinical form: Larazotide acetate Source
Clinical-program alias: AT-1001 Source
Free-peptide UNII: ZN3R5560ZV Source
Acetate UNII: FO8S2IW40N Source

Forms and derivatives

Larazotide and larazotide acetate

FDA maintains distinct identity records for the peptide and its monoacetate salt. The cited celiac-disease trials used larazotide acetate. A substance identity record helps identify the form but does not establish approval or clinical equivalence between preparations.

The biological rationale begins with the cells lining the intestine. Their junctions regulate passage between neighboring cells while the tissue absorbs nutrients and interacts with the immune system. Researchers proposed that preserving this barrier could reduce part of the response to gluten in celiac disease. That proposal led first to barrier experiments, then to studies using gluten challenge and studies of people with symptoms despite a gluten-free diet.

Uses and research areas

The main clinical program studied celiac disease in two settings. Gluten-challenge trials introduced a defined exposure under a research protocol and measured symptoms, intestinal permeability and immune markers. A later phase 2 trial studied adults with ongoing symptoms who continued their gluten-free diet. The second setting is closer to the question of an additional treatment for residual symptoms, and it became the focus of the phase 3 program. Leffler and colleagues (2012), Kelly and colleagues (2013), Leffler and colleagues (2015).

Barrier biology has also motivated trials in postinfectious illness. Massachusetts General Hospital registered studies in COVID-19-related multisystem inflammatory syndrome in children, or MIS-C, and Long COVID. These populations, outcomes and treatment contexts differ from the celiac program. Their current registry status is described in the research section. MIS-C registry, Long COVID registry.

Mechanism of action

Preserving the organization of the epithelial barrier

Tight junctions are protein assemblies near the upper edge of neighboring epithelial cells. They are connected to actin, part of the cell's internal supporting network. Changes in that network and the location of junctional proteins can make a cell layer more permeable. In Caco-2 and IEC6 cultures, Gopalakrishnan and colleagues used gliadin fragments, cytokines and the distinct permeability-inducing peptide AT-1002 to disrupt this organization. Larazotide acetate limited the movement of actin and the junction-associated protein ZO-1, preserved electrical resistance and reduced passage across the cell layer. The study also found preservation of junction structure in gliadin-sensitized HLA-HCD4/DQ8 mice. Gopalakrishnan and colleagues (2012).

A companion paper examined the assembly of junctions. Larazotide promoted reassembly in a calcium-switch experiment in MDCK cells, where changing calcium conditions allows investigators to dismantle and then restore cell contacts. It also improved junctional organization and reduced passage between cells in a relatively permeable Caco-2 model. Together, the papers describe effects on both disruption and formation of the barrier. They measure cell-layer structure and function; the clinical trials must separately establish whether those effects produce sustained symptom or tissue benefits. Gopalakrishnan and colleagues (2012).

Pharmacokinetics

Larazotide's intended intestinal action makes local exposure important. The oral clinical preparation is meant to encounter the epithelial surface, and the barrier experiments show activity when it is applied to the side of the cell layer facing the intestinal lumen. A useful exposure study would characterize the intact peptide at that site, its breakdown products and any systemic absorption. A blood measurement alone would cover only part of that question. Gopalakrishnan and colleagues (2012).

The acquired sources supply no verified elimination half-life with the preparation, route, population and measured analyte needed for a concentration–time illustration. Peptide length and a proposed local mechanism cannot determine that value. The absence of a verified curve also prevents treating a laboratory incubation period or a trial's treatment duration as the time the intact peptide remains active in a person.

Research findings

Gluten challenge produced mixed clinical measurements

Leffler's 2012 randomized, double-blind study assigned 86 diet-controlled patients to active treatment or placebo, with or without a 14-day gluten challenge. The main measurement was the urinary lactulose-to-mannitol ratio, an indirect assay of intestinal permeability. Values varied substantially, and neither the challenge-versus-control comparison nor active treatment versus placebo established a significant difference on that endpoint. Some lower treatment groups had less symptom worsening. The result supported further symptom research while leaving the intended permeability effect unresolved in this outpatient assay. Leffler and colleagues (2012).

Kelly's exploratory trial reported 184 participants and used a six-week gluten challenge. Again, the permeability assay did not significantly distinguish larazotide from placebo. The lowest active group, identified as the 1-mg arm, had less gastrointestinal symptom worsening (P=0.002), and active groups had smaller increases in anti-tissue-transglutaminase antibodies. Those antibody measurements describe immune reactivity. The trial's combination of favorable symptoms and immune markers with a negative permeability comparison shows why these outcomes need to be read separately. Kelly and colleagues (2013).

Persistent symptoms on a gluten-free diet

The 2015 multicenter trial randomized 342 adults with persistent celiac symptoms despite at least 12 months on a gluten-free diet. Participants continued that diet during 12 weeks of treatment. The modified intention-to-treat analysis included 340 people. The lowest active arm, 0.5 mg, met the primary symptom-score comparison with placebo (ANCOVA P=0.022), while the 1- and 2-mg arms showed no advantage on any endpoint. An exploratory analysis reported 26% fewer symptomatic days in the lowest arm. The absence of benefit in both higher arms makes the result harder to explain as a consistent exposure–response relationship. Leffler and colleagues (2015).

The main outcome was reported gastrointestinal symptoms. That is clinically relevant for someone who remains symptomatic, but the design did not establish that larazotide permits unrestricted gluten intake or prevents villous injury. Those claims would require direct, adequately controlled tissue and exposure outcomes.

The phase 3 celiac program was discontinued

In June 2022, 9 Meters Biopharma reported a prespecified interim sample-size reassessment of its CedLara phase 3 trial. Based on the observed data, the company concluded that the additional enrollment needed to detect a significant clinical difference from placebo was too large to support continuing. The official registry records the study as terminated by the sponsor, with 307 participants actually enrolled. This is a consequential failure of the clinical development program to establish its intended benefit. The sponsor's report does not provide the complete arm-level efficacy and safety results needed to independently reconstruct the interim analysis. 9 Meters announcement (2022).

Later registered studies

The MIS-C trial was terminated because cases declined; the registry lists 12 participants. That reason differs from an efficacy-driven discontinuation. The phase 2 Long COVID trial is listed as completed, with 107 participants and an actual completion date of June 18, 2026. Its August 2026 registry update has no posted results. The planned symptom and safety outcomes therefore remain a research question in the accessible record as of October 13, 2026. MIS-C registry, Long COVID registry.

Safety and tolerability

The published celiac trials generally reported tolerability similar to placebo. The 14-day study reported no serious adverse events; headache and urinary tract infection were the most common recorded events. The six-week challenge trial reported similar adverse-event rates between groups, and the 12-week persistent-symptom trial described safety as comparable with placebo. These observations concern the studied oral clinical formulations and follow-up periods. They provide limited information about uncommon reactions and longer exposure. Leffler and colleagues (2012), Kelly and colleagues (2013), Leffler and colleagues (2015).

Larazotide remains investigational, with no FDA-approved medicinal product identified in this review. FDA's December 2025 warning letter to Darmerica lists larazotide acetate among active pharmaceutical ingredients ineligible for human-drug compounding under section 503A. A supplier listing or FDA substance identifier does not establish an approved treatment. The warning letter addresses that firm's distribution and the applicable compounding provisions; it supplies no clinical safety clearance. FDA warning letter, FDA acetate identity record.

What the research means

Larazotide provides a well-developed example of a barrier-directed hypothesis reaching patient trials. The laboratory findings explain why investigators pursued it. The clinical findings show that symptom changes, immune markers and a permeability assay can point in different directions, even within the same trial. The positive low-dose phase 2 result justified a larger test, whose discontinuation materially changes the assessment of clinical promise.

The current evidence supports continued investigation of particular populations and outcomes. It leaves an established additional treatment for celiac disease unconfirmed, and the acquired Long COVID record adds no completed efficacy result. A future report would be most useful if it explained the complete tested preparation, baseline disease activity, prespecified outcomes, between-group effect and follow-up safety. Those details would show whether a benefit is reproducible and clinically meaningful.

FAQs

Did larazotide work in the celiac-disease trials?

The studies produced mixed results. Some lower-exposure groups improved symptoms, while the main permeability comparisons in the gluten-challenge trials did not succeed. A later phase 2 trial found symptom benefit in one arm and none in the two higher arms. The phase 3 program was discontinued after an interim assessment judged the additional required enrollment too large. The research findings describe how those results fit together.

Why can symptoms improve while the permeability test stays negative?

The trials asked participants about symptoms and also measured how much of two swallowed sugars appeared in urine, an indirect test of passage through the intestinal barrier. These measurements describe different aspects of the disease. The urine test varied substantially in the short gluten-challenge study, and the trials did not establish that larazotide improved it. Some symptom comparisons were favorable, but they do not establish protection of the intestinal lining.

Would larazotide let someone with celiac disease eat gluten safely?

The cited trials do not establish that. Their symptom and immune-marker results did not demonstrate prevention of gluten-related villous injury. The persistent-symptom study continued participants' gluten-free diets, so its result concerns an additional investigational intervention in that setting.

Why did the phase 3 program stop?

The sponsor reported that a prespecified interim sample-size reassessment indicated that too many additional participants would be needed to establish a significant clinical difference. The registry records termination by the sponsor. Complete arm-level results were not available in the acquired sources, which limits independent reconstruction of the analysis.

Has larazotide's Long COVID trial reported a benefit?

The official NCT05747534 record, checked October 13, 2026, lists the study as completed with 107 participants. No results were posted. Completion describes study progress; it leaves the treatment effect and safety findings awaiting a report.

Are AT-1001 and AT-1002 the same peptide?

The barrier papers use AT-1001 for larazotide acetate. AT-1002 is a separate permeability-inducing experimental peptide. Researchers used it to challenge the epithelial barrier and examine whether larazotide preserved cell-layer function.

Is larazotide FDA-approved?

No FDA-approved larazotide medicinal product was identified in this review. FDA's December 2025 warning letter specifically lists larazotide acetate among ingredients ineligible for human-drug compounding under section 503A. Its FDA substance identifier records identity and carries no approval.

Does a local intestinal mechanism imply a known half-life?

Local action describes where a treatment is intended to work. A half-life describes how long a measured concentration takes to fall by half, so researchers must specify what they measured and where. The reviewed larazotide studies did not provide the preparation-specific concentration measurements needed to establish that value or draw a reliable curve.

KPV has been studied through small-peptide transport and inflammatory signaling in cell and mouse colitis systems. Comparing it with larazotide highlights two different biological approaches to intestinal disease and the extra questions introduced by clinical trials. The barrier's role can be studied directly, while a patient trial must also determine how much it explains the person's symptoms and disease activity.

References

The sources include original barrier studies, celiac-disease trials, official registries, a sponsor-issued discontinuation report and FDA identity and regulatory records. The two 2012 barrier papers are separate publications with adjacent DOI numbers.

Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, Paterson BM, Murray JA, Verdu EF, Alkan SS, Pandey NB. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012;35(1):86–94. DOI: 10.1016/j.peptides.2012.02.015.
Tests barrier disruption in epithelial cultures and sensitized mice, including junction structure, resistance and movement across the cell layer.
Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, Paterson BM, Murray JA, Verdu EF, Alkan SS, Pandey NB. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012;35(1):86–94. DOI: 10.1016/j.peptides.2012.02.015. Original publisher record.
The original publisher record of the barrier-regulation paper indexed as PMID22401908, describing epithelial-junction organization and permeability in the tested models.
Gopalakrishnan S, Tripathi A, Tamiz AP, Alkan SS, Pandey NB. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides. 2012;35(1):95–101. DOI: 10.1016/j.peptides.2012.02.016.
Studies junction assembly in MDCK and Caco-2 models and relates protein organization to passage between cells.
Leffler DA, Kelly CP, Abdallah HZ, Colatrella AM, Harris LA, Leon F, Arterburn LA, Paterson BM, Lan ZH, Murray JA. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. The American journal of gastroenterology. 2012;107(10):1554–1562. DOI: 10.1038/ajg.2012.211.
A 14-day randomized gluten-challenge study with a variable permeability endpoint and symptom findings in selected lower treatment arms.
Kelly CP, Green PH, Murray JA, Dimarino A, Colatrella A, Leffler DA, Alexander T, Arsenescu R, Leon F, Jiang JG, Arterburn LA, Paterson BM, Fedorak RN, Larazotide Acetate Celiac Disease Study Group. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Alimentary pharmacology & therapeutics. 2013;37(2):252–262. DOI: 10.1111/apt.12147.
A six-week challenge trial reported symptom and antibody differences while finding no significant permeability-assay advantage.
Leffler DA, Kelly CP, Green PH, Fedorak RN, DiMarino A, Perrow W, Rasmussen H, Wang C, Bercik P, Bachir NM, Murray JA. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015;148(7):1311–1319.e6. DOI: 10.1053/j.gastro.2015.02.008.
The persistent-symptom phase 2 study found benefit in its lowest active arm and no benefit in either higher arm.
9 Meters Biopharma, Inc. Study to Evaluate the Efficacy and Safety of Larazotide Acetate for the Relief of CeD Symptoms. ClinicalTrials.gov NCT03569007. Last update posted July 26, 2022; official API checked October 13, 2026.
Records the phase 3 celiac study as terminated by the sponsor and lists 307 participants actually enrolled.
9 Meters Biopharma, Inc. 9 Meters Biopharma Announces Interim Analysis of Phase 3 Study of Larazotide for Celiac Disease Does Not Support Trial Continuation. Sponsor press release, June 21, 2022.
Explains the sponsor's decision following an interim sample-size reassessment; complete trial results are not included.
Massachusetts General Hospital. AT1001 for the Treatment of COVID-19 Related MIS-C. ClinicalTrials.gov NCT05022303. Last update posted June 13, 2024; checked October 13, 2026.
The pediatric postinfectious trial was terminated because cases declined; the record lists 12 actual participants.
Massachusetts General Hospital. AT1001 for the Treatment of Long COVID. ClinicalTrials.gov NCT05747534. Last update posted August 18, 2026; official API checked October 13, 2026.
Records a completed phase 2 study with 107 actual participants. No study results were posted at the research date.
U.S. Food and Drug Administration. Larazotide: UNII ZN3R5560ZV. Substance Registration System. Checked October 13, 2026.
Identifies the free peptide and its systematic sequence mapping.
U.S. Food and Drug Administration. Larazotide Acetate: UNII FO8S2IW40N. Substance Registration System. Checked October 13, 2026.
Distinguishes the acetate salt and AT-1001 identity; the registry explicitly separates substance identification from approval.
U.S. Food and Drug Administration. Darmerica, LLC: Warning Letter 320-26-24, MARCS-CMS 716152. December 8, 2025.
Specifically lists larazotide acetate among ingredients ineligible for human-drug compounding under section 503A.

Glossary

Tight junction: A protein assembly connecting neighboring epithelial cells and regulating passage between them.
Paracellular permeability: How readily material passes through the spaces between neighboring cells.
Actin: A protein that forms part of a cell's internal supporting network and contributes to cell-contact organization.
Gliadin: A group of wheat gluten proteins used in several of the barrier experiments.
Lactulose-to-mannitol ratio: A urine-based research measure comparing the passage of two sugars through the intestine.
Villous injury: Damage to the small intestine's fingerlike absorbing structures, a tissue feature of celiac disease.
Modified intention-to-treat analysis: An analysis of a trial's prespecified eligible randomized participants; its denominator can differ from the total randomized.
Sample-size reassessment: A planned analysis using accumulated trial data to estimate how many participants would be needed for a reliable treatment comparison.