Larazotide (AT-1001, Larazotide Acetate)
Larazotide (AT-1001) — the tight-junction "leaky gut" peptide that reached Phase 3 and failed: the honest story

Class: peptide
Synonyms: Larazotide
larazotide acetate
AT-1001
INN-202
Function tags: intestinal barrier / tight-junction regulation
celiac disease (adjunct, investigational)
"leaky gut" (the concept it actually targets)
gut health
Overall evidence grade: B
WADA prohibited: no
Last updated: 2026-07-13

In brief: Larazotide (AT-1001) is a synthetic octapeptide and a first-in-class "tight-junction regulator" — the first drug ever aimed at intestinal permeability, the "leaky gut" concept. Taken orally and acting only inside the gut, it works as a zonulin antagonist: in celiac disease, gluten makes the junctions between intestinal cells spring open (via zonulin), letting gliadin through to trigger the immune attack — and larazotide is designed to hold those junctions shut. It's genuinely notable for how far it got: developed across three companies (Alba → Innovate → 9 Meters), it became the most clinically advanced non-dietary celiac drug, the only Phase 3-stage one, with FDA Fast Track and positive Phase 2b data. But in June 2022 its pivotal Phase 3 (CeDLara) was stopped for futility — an interim analysis showed it couldn't feasibly beat placebo — a major blow to the whole zonulin/"leaky gut" drug hypothesis. As of 2026 it's approved for nothing. The honest, and broadly important, takeaway: the most rigorously developed "leaky gut" drug in history failed its decisive trial — which should temper the far larger, far less tested wellness-market hype around "leaky gut" supplements. A real drug, a real mechanism, a real (negative) answer.

## Identity a **synthetic single-chain octapeptide** (8 amino acids) that is a **first-in-class intestinal tight-junction regulator** — the **first drug ever to target intestinal permeability ("leaky gut") as a therapeutic mechanism.** It's **orally administered and "gut-restricted"** (acts locally in the intestinal lumen, essentially not absorbed systemically), developed as an **adjunct to the gluten-free diet** for **celiac disease**. Structurally related to cholera's **Zot** toxin (which *opens* junctions); larazotide is designed to help *close* them. ## Mechanism (as proposed) the intestinal epithelium is sealed by **tight junctions** — protein complexes (**claudins, occludin, ZO-1**) that control what passes *between* cells (the **paracellular** route). In celiac disease, gliadin triggers **zonulin** release, which **signals the tight junctions to disassemble**, increasing **permeability** and letting gliadin reach the immune cells beneath — driving inflammation. **Larazotide** is a **zonulin receptor antagonist** that **blocks this opening**, promoting **redistribution/reassembly of tight-junction proteins and actin filaments** (partly via **myosin-light-chain-kinase inhibition**, which relaxes the actin tension that pulls junctions apart) — thereby **restoring/maintaining barrier integrity.** Being **gut-restricted**, it does this **locally** with minimal systemic exposure (a safety advantage). The mechanism is coherent and animal-validated — and yet **the Phase 3 clinical endpoint wasn't met**, the register's recurring reminder that **a beautiful mechanism and even positive Phase 2 data don't guarantee pivotal success.**

Evidence grades by outcome:
outcome: Celiac disease (the lead, best-studied use)
grade: D
base: Positive Phase 2b (342 pts) → but Phase 3 CeDLara discontinued for futility (2022)
caveat: The defining fact: reached Phase 3 and failed — couldn't feasibly beat placebo. Not "untested" — tested and negative at the pivotal stage
outcome: Tight-junction / permeability mechanism
grade: C
base: Well-characterized: zonulin antagonism; MLCK inhibition; rodent + porcine barrier-repair models
caveat: The biology of tight-junction regulation is real and elegant; it didn't translate to a positive clinical endpoint
outcome: "Leaky gut" / general gut health (the gray-market pitch)
grade: F
base: No approved indication; concept-level only
caveat: The broad wellness claim is not supported; even the targeted celiac trial failed
outcome: Adjacent indications (MIS-C, intestinal ischemia)
grade: F
base: Early/preclinical (porcine ischemia repair, pediatric research)
caveat: Exploratory; nothing established
outcome: Safety
grade: B
base: Extensive trial exposure; gut-restricted (minimal systemic absorption)
caveat: Generally well-tolerated in trials (a genuine plus — its problem was efficacy, not safety); long-term chronic-modulation effects unestablished

Legal status:
region: US
status: Not approved
note: not approved for any indication (the Phase 3 celiac program failed in 2022). It had FDA Fast Track during development, but never reached approval. Investigational.

Cosmetic claims:

Note: The "leaky gut" drug that got furthest — and still failed Phase 3. Larazotide is unusual in this register: a first-in-class, FDA Fast-Tracked, Phase 3-stage pharmaceutical — the most clinically advanced non-dietary celiac-disease drug ever — not a typical gray-market peptide. Three threads: (1) its mechanism is genuinely novel — it's the first drug to target intestinal permeability ("leaky gut") by tightening the junctions between gut cells; (2) it reached Phase 3 with positive Phase 2 data and a real pipeline; (3) in June 2022 that Phase 3 was discontinued for futility — a major setback for the whole zonulin/"leaky gut" pharmacologic hypothesis. The most-developed leaky-gut drug in history couldn't beat placebo — a sobering fact for the supplement hype around the same concept.
Status note: status: celiac Phase 3 failed 2022, no approved indication; watch only for revived development in adjacent barrier-disease indications

Sources:
Slifer ZM, Krishnan BR, Madan J, Blikslager AT. Larazotide acetate: a pharmacological peptide approach to tight junction regulation. Am J Physiol Gastrointest Liver Physiol. 2021 (mechanism; zonulin/MLCK).
Phase 2b (Alba Therapeutics, 2014; 342 patients) — reduced symptoms; non-monotonic dose response.
CeDLara Phase 3 (CeD-LA-3001, 525 patients): discontinued for futility, June 2022 (9 Meters Biopharma press release; BioSpace, BeyondCeliac coverage) — interim analysis, couldn't feasibly beat placebo.
Fasano A, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000 (the zonulin concept). Porcine ischemia tight-junction repair (2021). (No FDA approval as of 2026; celiac program halted.)