Larazotide: The Zonulin Antagonist That Reached Phase 3
An oral zonulin antagonist that holds the gut's tight junctions shut against gluten — a celiac-disease drug candidate, not a general gut-health peptide.
What is Larazotide?
Larazotide is an oral octapeptide zonulin antagonist, designed to tighten the gut's paracellular tight junctions and block the intestinal permeability response triggered by gluten in celiac disease. A positive Phase 2 trial (0.5mg three times daily) reduced persistent celiac symptoms, but the pivotal Phase 3 trial, CeDLara, was terminated in 2022 after a futility interim analysis, and the development program was discontinued. There is no evidence supporting its use for general 'leaky gut' or gut-health claims outside celiac disease specifically.
Quick facts
- Class
- Oral zonulin antagonist / tight-junction regulator (octapeptide)
- Solubility
- Oral capsule — no reconstitution required
- Brand Names
- No trademarked brand — clinical development discontinued before reaching market
- Legal Status
- Not FDA-approved — Phase 3 program (CeDLara) terminated in 2022. Sold RUO
- Category
- Gut Health
- Storage
- Room temperature, sealed, away from light and moisture. No refrigeration or reconstitution required.
Dosing at a glance
Doses shown are those reported in published research, not a recommendation.
What the evidence supports
| Claim | Grade | Basis |
|---|---|---|
| Gut Health | Dgrade | Celiac-specific; positive Phase 2 (Leffler 2015), Phase 3 terminated for futility in 2022. |
Larazotide Mechanism of Action
Blocking the Zonulin Pathway
Larazotide is a zonulin antagonist — zonulin is the endogenous signal that loosens the tight junctions between intestinal epithelial cells, and gluten exposure triggers excess zonulin release in people with celiac disease. By blocking this pathway, larazotide is designed to keep the gut's tight junctions shut, limiting the permeability spike (and downstream immune activation) that gluten exposure causes.
A Celiac Drug, Not a General Gut-Health Peptide
Larazotide acts locally in the gut lumen rather than being systemically absorbed, which is part of its safety appeal as an oral drug candidate. Critically, it was developed and studied specifically for celiac disease — there is no evidence it addresses general 'leaky gut' or non-celiac gut-health concerns, despite how it's sometimes marketed.
Larazotide Dosage and Protocols
Phase 2 Trial Dosing
The only dose with meaningful supporting data is 0.5mg orally, three times daily — the regimen used in the positive Phase 2 trial. Higher doses tested in the same trial showed no additional benefit. No FDA-approved or otherwise validated dosing schedule exists beyond this trial protocol.
Larazotide Side Effects and Safety
Generally Well-Tolerated in Trials
Larazotide acts locally in the gut and is minimally systemically absorbed, which is part of why it was generally well-tolerated in trials, with mild GI effects (bloating, discomfort) most commonly reported. Comprehensive long-term safety data beyond the discontinued trial program doesn't exist.
Larazotide Research Evidence
A Positive Phase 2 That Didn't Carry Through
In a 2015 Phase 2 trial (Leffler et al., Gastroenterology, n=342), larazotide at 0.5mg three times daily reduced persistent celiac symptoms compared to placebo in patients already on a gluten-free diet — notably, higher doses performed no better. This positive signal supported advancement to Phase 3.
Phase 3 Termination and Regulatory and Legal Status
The pivotal Phase 3 trial, CeDLara, was terminated in 2022 at a pre-planned futility interim analysis — it could not reach statistical significance, and the development program was discontinued. Larazotide is not FDA-approved and has no path to market as things stand. It is sold today only as a research-grade compound (RUO); researchers and users should verify the legal status of larazotide in their jurisdiction prior to purchase or use.
Larazotide Stacking and Combinations
Standalone Gut-Barrier Research
Larazotide is studied and used as a standalone gut-barrier compound rather than combined with other peptides — its mechanism (local tight-junction modulation) doesn't have an established synergistic pairing with systemic peptides like BPC-157.
Larazotide Pharmacokinetics
Designed for Local, Not Systemic, Action
Larazotide's mechanism depends on acting locally within the gut lumen at the tight-junction level, rather than systemic absorption and circulation — a conventional plasma half-life isn't the relevant pharmacokinetic parameter here the way it is for injectable peptides.
Contraindications
- pregnancy
- known hypersensitivity
Trials and reviews
- Leffler celiac Phase 2Gastroenterology2015
0.5mg TID reduced persistent celiac symptoms vs. placebo (n=342)
- CeDLara Phase 3 (terminated)9 Meters Biopharma2022
Terminated at a pre-planned futility interim; program discontinued
Frequently asked questions
What is a typical Larazotide dose?
Published research protocols report 0.5 mg, 3x daily. This is the range described in the literature, not a recommendation.
What is the half-life of Larazotide?
Not established — designed to act locally in the gut lumen rather than systemically.
Is Larazotide backed by strong evidence?
Larazotide carries a REGEN research grade of D. REGEN Research Tier D — a positive Phase 2 that did not carry through to Phase 3.
How is Larazotide administered?
Routes reported in the literature: oral.
Who should avoid Larazotide?
Contraindications noted in the literature include pregnancy, known hypersensitivity.
References
- Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet · Leffler DA, et al. · 2015