Larazotide: Intestinal Permeability Research
For the roughly 3 million Americans with celiac disease, the only approved treatment is a lifelong gluten-free diet. No pill, no injection, no pharmaceutical backup.
For the roughly 3 million Americans with celiac disease, the only approved treatment is a lifelong gluten-free diet. No pill, no injection, no pharmaceutical backup. Just relentless dietary vigilance — reading every label, interrogating every restaurant server, and hoping that trace contamination does not trigger another round of bloating, pain, and diarrhea.
Even with strict adherence, it often is not enough. Studies show that 30% to 50% of celiac patients on a gluten-free diet continue to experience persistent symptoms. The problem is not just what gets into the gut. It is what leaks through it. When the intestinal lining loses its seal — a condition researchers call increased intestinal permeability — gliadin fragments slip past the barrier and ignite the immune response all over again.
Larazotide acetate was built to address that problem. A synthetic peptide of just eight amino acids, it was designed to reinforce the gates between intestinal cells, blocking the molecular pathway that pries them open. It became the first drug candidate of its kind to reach Phase 3 clinical trials for celiac disease. The story of how it got there, and what happened next, says a great deal about the science of "leaky gut," the difficulty of developing gut-targeted therapies, and the uncertain future of tight junction medicine.
Table of Contents
- Quick Facts
- What Is Larazotide?
- The Zonulin Connection
- How Larazotide Works: Mechanisms of Action
- Clinical Research
- Beyond Celiac Disease
- Administration and Dosing
- Safety Profile and Side Effects
- Legal and Regulatory Status
- Limitations of Current Research
- Frequently Asked Questions
- The Bottom Line
Quick Facts
| Property | Detail |
|---|---|
| Full Name | Larazotide acetate |
| Other Names | AT-1001, INN-202 |
| Type | Synthetic octapeptide (8 amino acids) |
| Amino Acid Sequence | Gly-Gly-Val-Leu-Val-Gln-Pro-Gly (GGVLVQPG) |
| Molecular Class | Tight junction regulator / zonulin antagonist |
| Origin | Derived from Vibrio cholerae zonula occludens toxin (Zot) |
| Route of Administration | Oral |
| Absorption | Non-systemic; acts locally in the small intestine |
| Primary Target | Intestinal epithelial tight junctions |
| Indication Studied | Celiac disease (adjunct to gluten-free diet) |
| FDA Designations | Fast Track (for celiac disease) |
| Clinical Stage | Phase 3 discontinued (June 2022) |
| Developer History | Alba Therapeutics > Innovate Biopharmaceuticals > 9 Meters Biopharma |
| Patients Studied | 800+ across all clinical trials |
| First Described | Wang et al., 2000 |
What Is Larazotide?
Larazotide is a synthetic peptide made of eight amino acids, originally developed by Alba Therapeutics, a company founded in 2004 to translate the emerging science of tight junction biology into medicine. The peptide's structure comes from an unlikely source: a toxin produced by the cholera bacterium, Vibrio cholerae.
That toxin — called zonula occludens toxin, or Zot — opens the tight junctions between intestinal cells, which is one reason cholera causes such severe diarrhea. Researchers studying Zot identified a specific eight-amino-acid sequence (GGVLVQPG) near its active region that matched a portion of zonulin, the human protein that naturally regulates tight junction permeability.
The logic was counterintuitive but precise: by synthesizing a peptide that mimicked the receptor-binding region of zonulin, they could create a molecule that competes with zonulin for its receptor without activating the downstream signaling that opens tight junctions. In pharmacological terms, larazotide is a competitive antagonist. It sits in the lock but does not turn it.
What makes larazotide unusual among therapeutic peptides is that it was designed not to be absorbed. Most peptide drugs need to reach the bloodstream to work. Larazotide does its job on the luminal surface of the small intestine — the side that faces food — and is broken down locally. No detectable drug reaches the blood. This "topical" approach to the gut lining is why it has such a clean safety profile across trials.
For readers interested in other peptides studied for gut health, BPC-157 works through entirely different mechanisms (angiogenesis and growth factor signaling) but shares the trait of gastric stability and oral potential.
The Zonulin Connection
To understand why larazotide exists, you need to understand zonulin — and the researcher who found it.
In 2000, Alessio Fasano and colleagues at the University of Maryland published a discovery in The Lancet that reshaped how scientists think about intestinal permeability. They identified a human protein that reversibly regulates the tight junctions between intestinal epithelial cells. They named it zonulin, after the bacterial toxin (Zot) that had led them to it.
Tight junctions are the seals between adjacent intestinal cells. They are not static walls — they open and close dynamically, controlled by a network of proteins including occludin, claudins, and zonula occludens proteins (ZO-1, ZO-2, ZO-3). This selective permeability allows nutrients through while keeping bacteria, toxins, and undigested food fragments out.
Zonulin disrupts that barrier. When released by intestinal cells in response to certain triggers — gluten (specifically gliadin peptides) and certain bacteria being the two best-documented — zonulin binds to receptors on the cell surface (EGFR and PAR2). This triggers a signaling cascade that reorganizes the actin cytoskeleton inside cells and displaces tight junction proteins from their positions. The junctions loosen. The barrier opens.
In celiac disease, this process runs in overdrive. Gliadin binds to the chemokine receptor CXCR3 on intestinal epithelial cells, triggering zonulin release through a MyD88-dependent pathway. Zonulin opens tight junctions, allowing gliadin fragments to pass through to the lamina propria — the immune-active tissue beneath the epithelium. There, these fragments meet tissue transglutaminase, get modified, and are presented to immune cells that mount the inflammatory attack that defines celiac disease.
Fasano's later work, published in PNAS in 2009, identified zonulin as the precursor of haptoglobin-2 (pre-HP2). Studies found that celiac patients had significantly elevated zonulin levels compared to healthy controls.
The therapeutic implication was clear: block zonulin from opening tight junctions, and you might reduce the inflammatory damage in celiac disease — even when small amounts of gluten slip through a gluten-free diet. That idea became larazotide.
How Larazotide Works: Mechanisms of Action
Larazotide's mechanism centers on blocking the zonulin-mediated opening of intestinal tight junctions. But recent research suggests it does more than occupy a receptor.
Zonulin Receptor Antagonism
The primary mechanism is competitive inhibition. Larazotide competes with zonulin for binding to EGFR and PAR2 on intestinal epithelial cells, preventing the downstream cascade — phospholipase C activation, protein kinase C-alpha signaling, and the actin polymerization that dismantles tight junctions.
In simpler terms: when gliadin triggers zonulin release, larazotide is already sitting where zonulin needs to bind. The signal to open the gates never gets through.
Tight Junction Assembly Promotion
Larazotide does not just block disassembly — it appears to actively promote tight junction assembly. In cell culture studies using MDCK type II cells, larazotide promoted the redistribution of E-cadherin and actin to tight junction complexes, reinforcing the existing barrier architecture.
Myosin Light Chain Kinase Inhibition
More recent work has linked larazotide to inhibition of myosin light chain kinase (MLCK), an enzyme that increases tension on actin filaments attached to tight junction proteins. By reducing this tension, larazotide facilitates tight junction closure — a mechanism independent of the zonulin pathway, suggesting multiple routes of barrier protection.
Protection Against Ischemic Injury
A 2025 study found that larazotide protected the intestinal mucosal barrier against anoxia/reoxygenation injury through various cellular mechanisms beyond zonulin antagonism, expanding the picture of how the peptide works.
The combined effect is a peptide that both prevents barrier breakdown and actively supports barrier maintenance — distinguishing it from drugs that simply suppress immune responses downstream.
Clinical Research
Phase 1: Safety in Healthy Volunteers
Two Phase 1 trials tested single and multiple doses from 0.25 mg to 36 mg in healthy volunteers. No severe drug-related adverse events occurred, and no participant withdrew. Headache was the most commonly reported symptom, at rates similar to placebo. No drug was detected in blood plasma at any dose, confirming the non-systemic profile.
Phase 2: Gluten Challenge Studies
The first celiac patient trial used a gluten challenge model. Patients received either a single 12 mg dose of larazotide or placebo, followed by deliberate gluten exposure. Larazotide-treated patients showed less intestinal permeability dysfunction, lower interferon-gamma production, and fewer gastrointestinal symptoms.
A larger dose-ranging study enrolled 86 patients randomized to larazotide (0.25, 1, 4, or 8 mg) or placebo three times daily, with or without a daily 2.4-gram gluten challenge. Lower doses reduced intestinal permeability and blunted rises in anti-tissue transglutaminase antibodies.
An inverse dose-response emerged: lower doses appeared more effective than higher ones. One hypothesis is that higher concentrations aggregate in the gut lumen, reducing effective receptor interaction.
Phase 2b: The CeliAction Study
The CeliAction study, published in Gastroenterology in 2015 by Leffler, Kelly, Green, Murray, and colleagues, was the largest trial in larazotide's development. This multicenter, randomized, double-blind, placebo-controlled trial enrolled 342 adults with celiac disease on a gluten-free diet for at least 12 months who continued to experience symptoms. Patients were randomized to larazotide acetate at 0.5 mg (n=86), 1 mg (n=85), or 2 mg (n=87) three times daily, or placebo (n=84), for 12 weeks across 74 North American sites.
Results at the 0.5 mg dose:
- Primary endpoint met: significantly fewer symptoms on the CeD-GSRS compared to placebo (ANCOVA P = 0.022; MMRM P = 0.005)
- 26% decrease in symptomatic days versus placebo (P = 0.017)
- 31% increase in improved symptom days (P = 0.034)
- 29% of patients achieved at least 50% reduction in weekly abdominal symptom scores for 6+ of 12 treatment weeks, versus 14% with placebo
The 1 mg and 2 mg doses did not outperform placebo on the primary endpoint, reinforcing the inverse dose-response pattern. This made larazotide the first and only drug to meet its primary endpoint with statistical significance in a Phase 2b celiac disease trial. The FDA subsequently granted Fast Track designation.
Phase 3: The CeDLara Trial
The Phase 3 CeDLara trial (NCT03569007) launched in 2018 across more than 100 US and Canadian sites, enrolling 525 celiac patients randomized equally to larazotide 0.25 mg, 0.5 mg, or placebo. The primary endpoint was change from baseline in the CeD PRO abdominal domain score over 12 weeks.
In June 2022, 9 Meters Biopharma announced that a pre-planned interim futility analysis did not support continuing the trial. An independent statistician determined that the number of additional patients needed for statistical significance was too large to make the trial feasible.
Several factors may explain the Phase 2b-to-Phase 3 disconnect: the trial used a different primary outcome measure (CeD PRO rather than CeD-GSRS), patient-reported outcomes in celiac disease are notoriously variable, and the placebo response rate in celiac trials tends to be high. The Phase 2b effect size, while statistically significant, may not have been large enough to reproduce in a bigger, more diverse population.
Beyond Celiac Disease
The logic of tight junction regulation extends beyond a single autoimmune condition.
MIS-C (Multisystem Inflammatory Syndrome in Children)
The most striking data outside celiac came during the COVID-19 pandemic. Researchers at Massachusetts General Hospital and Brigham and Women's Hospital, led by Fasano, tested larazotide in children with MIS-C — a rare, severe inflammatory condition developing weeks after SARS-CoV-2 infection. Their hypothesis: viral particles lingering in the gut were leaking through compromised tight junctions, triggering systemic inflammation via the zonulin pathway.
In a small case series, children who received four daily oral doses of larazotide showed faster resolution of GI symptoms and slightly shorter hospital stays. Serum levels of the SARS-CoV-2 spike protein dropped to undetectable levels within one day in treated children, versus 10 days in controls. No adverse events were attributed to larazotide. The connection to Kawasaki disease — which shares clinical features with MIS-C and has been linked to zonulin-dependent intestinal permeability — further supported the mechanism.
Type 1 Diabetes and Autoimmune Conditions
Fasano's research showed that zonulin-dependent increases in intestinal permeability precede type 1 diabetes onset by two to three weeks in animal models. A 2021 review cataloged potential applications across multiple inflammatory and autoimmune conditions, including inflammatory bowel disease.
Environmental Enteropathy
Environmental enteropathy — chronic intestinal inflammation caused by repeated pathogen exposure in low-resource settings — affects gut barrier integrity in ways that overlap with the zonulin pathway, though larazotide has not been tested in this context.
For related research, KPV targets gut inflammation through anti-inflammatory mechanisms, VIP modulates GI function through different receptor systems, and our guide to the best peptides for gut health compares evidence across candidates.
Administration and Dosing
Larazotide is administered orally — notable for a therapeutic peptide, since most peptides are destroyed by stomach acid and require injection. Larazotide was designed to act on the luminal surface of the small intestine without needing systemic absorption.
Across all clinical trials, larazotide was given three times daily with meals:
| Trial Phase | Doses Tested | Most Effective Dose |
|---|---|---|
| Phase 1 (healthy volunteers) | 0.25–36 mg | Safety study only |
| Phase 2 (gluten challenge) | 0.25, 1, 4, 8 mg TID | Lower doses (0.25–1 mg) |
| Phase 2b (CeliAction) | 0.5, 1, 2 mg TID | 0.5 mg TID |
| Phase 3 (CeDLara) | 0.25, 0.5 mg TID | Discontinued before completion |
The optimal dose was consistently 0.5 mg three times daily. Higher doses did not produce better outcomes.
Researchers developed a delayed-release formulation targeting the duodenum and proximal jejunum, where celiac disease causes the most damage. In a porcine model study, oral dosing produced peak concentrations at approximately one hour, with the drug remaining at therapeutically relevant levels (0.02-1.76 micromolar) for several hours. Pharmacokinetic studies confirmed no systemic absorption — the peptide is broken down locally in the small intestine.
Safety Profile and Side Effects
Across more than 800 patients in Phase 1 through Phase 3 trials, larazotide has demonstrated a remarkably clean safety profile.
| Finding | Detail |
|---|---|
| Overall safety | Comparable to placebo across four clinical trials |
| Most common adverse event | Headache (similar rates in drug and placebo groups) |
| Other reported events | Fatigue, urinary tract infections, GI symptoms |
| Serious adverse events | None attributed to larazotide in any trial |
| Organ toxicity | No hepatic, renal, or bone toxicity observed |
| Cardiovascular effects | No significant ECG changes; FDA waived thorough QT study |
| Lab abnormalities | No clinically significant changes |
GI adverse events reported in trials were often difficult to distinguish from underlying celiac symptoms. In the CeliAction study, GI adverse event rates were similar between larazotide and placebo groups.
The explanation for this safety profile is straightforward: larazotide does not enter the blood. It acts only on the luminal surface of the intestinal epithelium and is degraded locally, eliminating the off-target effects that affect systemically absorbed drugs.
For perspective on peptide safety more broadly, our guides on LL-37 and peptides for inflammation reduction compare tolerability across peptide classes.
Legal and Regulatory Status
Larazotide's corporate journey has been as turbulent as its clinical one.
Development Timeline
- 2000: Wang et al. publish the GGVLVQPG sequence and demonstrate zonulin inhibition
- 2004: Alba Therapeutics founded to develop tight junction therapeutics
- 2007: Alba enters a $325 million ex-US licensing agreement with Shire
- 2009-2013: Phase 1 and Phase 2 trials completed
- 2015: CeliAction results published in Gastroenterology
- 2016: Innovate Biopharmaceuticals licenses all larazotide assets from Alba; FDA grants Fast Track designation
- 2020: 9 Meters Biopharma formed via merger of Innovate and RDD Pharma; Phase 3 CeDLara trial enrolling across 100+ sites
- June 2022: Phase 3 discontinued based on interim futility analysis
- July 2023: 9 Meters Biopharma files for Chapter 7 liquidation
Current Status
As of early 2026, there is no active clinical development program for larazotide. The Chapter 7 filing means 9 Meters was liquidated, not restructured. The intellectual property — patents, clinical data, formulation know-how — would have been handled through the bankruptcy process and could potentially be acquired by another company. No pharmaceutical company has publicly announced plans to resume development. Larazotide remains unapproved worldwide, unavailable by prescription, and not commercially manufactured.
Limitations of Current Research
The Phase 3 Failure
The most significant limitation is that larazotide did not demonstrate sufficient efficacy in its Phase 3 trial. The treatment effect may have been modest enough that it did not reproduce in a larger, more diverse population. High placebo response rates in celiac symptom trials — a well-known challenge — likely compounded the problem.
Outcome Measure Challenges
Celiac disease is difficult to study with patient-reported outcome measures. Symptoms overlap with irritable bowel syndrome, dietary indiscretions are hard to monitor, and the subjective nature of GI symptoms introduces noise. The switch from CeD-GSRS (Phase 2b) to CeD PRO abdominal domain (Phase 3) may have contributed to the different results.
The Zonulin Measurement Controversy
Studies from 2018 onward revealed that widely used commercial ELISA kits marketed for measuring serum zonulin do not actually detect zonulin (pre-haptoglobin-2). Instead, they detect unrelated proteins including properdin and complement C3. This does not invalidate larazotide's mechanism — its effects on tight junctions in cell culture and animal models are documented regardless of how serum zonulin is measured. But it means that published literature linking elevated "zonulin levels" to various diseases needs cautious interpretation. Fasano's group has proposed that these kits measure "zonulin family peptides" (ZFPs), a broader class of related proteins. The debate is unresolved.
Limited Disease Scope and No Commercial Sponsor
All completed clinical trials focused on celiac disease. The MIS-C data is from a small, uncontrolled case series. Applications in type 1 diabetes, IBD, and IBS remain theoretical. With 9 Meters Biopharma liquidated, larazotide has no company actively funding its development.
Frequently Asked Questions
What is larazotide acetate used for? Larazotide was developed as a treatment for celiac disease, intended to be used alongside — not instead of — a gluten-free diet. It is not currently approved for any use and has no active development program as of 2026.
How does larazotide differ from other celiac disease drugs in development? Most celiac drug candidates either degrade gluten before it reaches the intestine (glutenases like latiglutenase) or suppress the downstream immune response. Larazotide takes a different approach: it reinforces the intestinal barrier to prevent gluten fragments from crossing into immune-active tissue. This barrier-first strategy is unique in the celiac pipeline.
Is larazotide available to patients? No. It has not been approved by any regulatory agency and is not available by prescription or through compounding. Its former manufacturer filed for bankruptcy in 2023.
Why did the Phase 3 trial fail? The interim analysis showed that the difference between larazotide and placebo was too small to achieve statistical significance with a feasible number of patients. Contributing factors likely include high placebo response rates, a different primary outcome measure from Phase 2b, and the inherent difficulty of measuring subjective GI symptoms.
Can larazotide cure celiac disease? No. Even in its most optimistic framing, larazotide was designed as an adjunct to a gluten-free diet — not a replacement for it.
Is larazotide the same as "leaky gut" supplements? No. Larazotide is a pharmaceutical-grade synthetic peptide with a specific molecular target and eight completed clinical trials. Over-the-counter "leaky gut" supplements (L-glutamine, zinc, probiotics) work through different, less precisely defined mechanisms.
Could another company develop larazotide? It is possible. The intellectual property was likely sold through 9 Meters Biopharma's bankruptcy proceedings. However, resuming development would require significant investment, and the Phase 3 failure creates a higher bar for regulatory discussions.
The Bottom Line
Larazotide acetate represents one of the more scientifically rigorous attempts to target intestinal permeability as a therapeutic strategy. Its mechanism is well-characterized: a synthetic octapeptide that blocks zonulin-mediated tight junction opening, acts locally in the gut without systemic absorption, and demonstrated symptom reduction in a 342-patient Phase 2b trial at 0.5 mg three times daily.
It also represents the gap between promising biology and successful drug development. The Phase 3 failure and subsequent bankruptcy of its developer have left larazotide without an active clinical program. For the celiac disease community — 3 million Americans with no approved medication — this remains a painful setback.
The science has not been wasted. Larazotide proved that tight junction modulation is a viable pharmacological target. It demonstrated that an oral, non-absorbed peptide can reach the right cells in the gut and produce measurable clinical effects. And the MIS-C data, though preliminary, hints that the tight junction approach may have applications beyond celiac disease.
Whether larazotide returns to development depends on whether a pharmaceutical sponsor sees enough value in the existing data to try again — perhaps with a refined trial design, a better endpoint, or a more targeted patient population. The biology supports continuing. The business case is less clear.
What is clear: the era of treating intestinal permeability as a fringe concept is over. Zonulin, tight junctions, and the intestinal barrier are now part of mainstream gastroenterology. Larazotide helped make them so.
This article is for educational purposes only. Larazotide acetate is not approved by the FDA or any regulatory body. It is not available for purchase or prescription. Nothing in this article constitutes medical advice. Always consult a qualified healthcare provider for decisions about your health.