Larazotide：セリアック病第3相試験中のタイトジャンクション調節ペプチド
要約
- What it is: Larazotide acetate (AT-1001) is an eight-amino-acid synthetic peptide that regulates tight junction (TJ) integrity in the intestinal epithelium, derived from the Vibrio cholerae zonula occludens toxin (Zot) binding domain.
- Mechanism: Larazotide acts as a competitive antagonist of zonulin — the endogenous TJ modulator that increases intestinal permeability — preventing zonulin-driven tight junction disassembly.
- Clinical advancement: Larazotide has completed Phase 2b and entered Phase 3 clinical trials for celiac disease, making it one of the most clinically advanced peptides targeting intestinal permeability.
- Phase 2 results: The 0.5 mg TID dose reduced celiac symptoms and decreased anti-tissue transglutaminase (anti-tTG) antibody levels in gluten-exposed celiac patients on a gluten-free diet.
- Status: Phase 3 clinical trials ongoing/completed. Not yet FDA-approved. Developed by Innovate Biopharmaceuticals (now 9 Meters Biopharma).
For informational purposes only. This article does not constitute medical advice. Consult a qualified healthcare provider for any health-related decisions.
What Is Larazotide?
Larazotide acetate (development name AT-1001) is a synthetic octapeptide designed to regulate intestinal epithelial tight junction (TJ) function. It represents one of the most novel approaches to gastrointestinal disease treatment — rather than suppressing the immune response or treating symptoms, larazotide addresses the upstream mechanism of increased intestinal permeability ("leaky gut") that initiates and perpetuates the inflammatory cascade in celiac disease and potentially other conditions.
The compound was developed based on research by Dr. Alessio Fasano and colleagues at the University of Maryland Center for Celiac Research, who discovered zonulin — an endogenous human protein that modulates tight junction permeability. Larazotide is derived from the binding domain of Vibrio cholerae zonula occludens toxin (Zot), which mimics zonulin's tight junction-opening activity. By competitively antagonizing zonulin at the tight junction, larazotide prevents the permeability increase that allows immunogenic gliadin peptides to cross the intestinal barrier. For broader context on gut health peptides, see our guide to gut health peptides.
| Property | Detail |
|---|---|
| Generic Name | Larazotide acetate |
| Development Name | AT-1001 |
| Structure | Synthetic octapeptide |
| Mechanism | Tight junction regulator / zonulin antagonist |
| Route | Oral (capsule, acts locally in GI tract) |
| Systemic Absorption | Minimal (acts locally at intestinal epithelium) |
| Developer | 9 Meters Biopharma (formerly Innovate Biopharmaceuticals) |
| Clinical Stage | Phase 3 for celiac disease |
| FDA Status | Not yet approved; FDA Fast Track designation granted |
Mechanism of Action
Understanding larazotide's mechanism requires understanding the zonulin pathway and tight junction biology.
Tight Junction Biology
Tight junctions are the apical-most junctional complexes between adjacent epithelial cells, forming the primary barrier that regulates paracellular transport across the intestinal epithelium. They consist of transmembrane proteins (claudins, occludin, junctional adhesion molecules) linked to an intracellular scaffold (ZO-1, ZO-2, ZO-3) that connects to the actin cytoskeleton. Tight junction permeability is dynamically regulated, opening and closing in response to physiological and pathological signals.
The Zonulin Pathway
Zonulin (identified as pre-haptoglobin-2) is the only known physiological modulator of intestinal tight junctions. When gliadin peptides (from wheat gluten) contact the intestinal epithelium, they trigger zonulin release through CXCR3 receptor activation. Zonulin then binds to PAR2 (protease-activated receptor 2) and EGFR (epidermal growth factor receptor), activating intracellular signaling that leads to tight junction disassembly — specifically, phosphorylation of ZO-1 and myosin light chain, causing contraction of the perijunctional actin ring and physical separation of tight junction strands.
Larazotide's Competitive Antagonism
- Receptor competition: Larazotide competes with zonulin for binding at the tight junction regulatory site, preventing zonulin-induced signaling.
- TJ stabilization: By blocking the zonulin signal, larazotide prevents the phosphorylation cascade that leads to tight junction disassembly, maintaining barrier integrity.
- Local action: Larazotide acts on the luminal surface of the intestinal epithelium and is minimally absorbed systemically, giving it a favorable safety profile.
- Gliadin exclusion: By maintaining tight junction integrity, larazotide prevents the paracellular passage of immunogenic gliadin peptides across the intestinal barrier, reducing immune activation in celiac patients.
Research and Clinical Trials
Phase 1 Studies
Initial safety studies demonstrated that larazotide was well tolerated orally and had minimal systemic absorption. Ex vivo studies using intestinal tissue in Ussing chambers confirmed that larazotide prevented gliadin-induced increases in intestinal permeability.
Phase 2 Trials
Multiple Phase 2 trials have been conducted in celiac disease patients. The key findings include:
- In a Phase 2a study (gluten challenge model), larazotide reduced intestinal permeability changes and attenuated the immune response to gluten exposure compared to placebo.
- In the Phase 2b study (CeliAction), celiac patients on a gluten-free diet who received larazotide 0.5 mg three times daily showed significant reduction in symptoms (assessed by the Celiac Disease Gastrointestinal Symptom Rating Scale) and decreased anti-tTG IgA antibody levels compared to placebo.
- An inverted dose-response was observed — the lowest dose (0.5 mg TID) was most effective, while higher doses showed diminishing benefit, possibly due to receptor saturation or off-target effects at higher concentrations.
Phase 3 Development
Based on Phase 2 results, larazotide received FDA Fast Track designation for celiac disease and advanced to Phase 3 trials. The Phase 3 program targets symptomatic celiac disease patients who experience persistent symptoms despite adherence to a gluten-free diet — a population estimated at 30–50% of celiac patients, for whom no approved pharmacological treatment currently exists.
Beyond Celiac Disease
The zonulin pathway and increased intestinal permeability have been implicated in numerous conditions beyond celiac disease, including type 1 diabetes, inflammatory bowel disease, irritable bowel syndrome, and even neurological conditions. While larazotide's clinical development has focused on celiac disease, successful validation of the tight junction-targeting approach could open doors for investigation in other permeability-related conditions.
Safety and Tolerability
Larazotide has demonstrated an excellent safety profile across multiple clinical trials. Because the peptide acts locally at the intestinal epithelium with minimal systemic absorption, systemic adverse effects are limited. The most commonly reported adverse effects were headache, upper respiratory tract infection, and gastrointestinal symptoms (nausea, abdominal pain) — with rates similar to placebo in most studies. No serious drug-related adverse events have been reported in the clinical trial program.
Regulatory Status
Larazotide has received FDA Fast Track designation for the treatment of celiac disease in patients who are symptomatic despite adherence to a gluten-free diet. It has not yet received FDA approval. If approved, larazotide would be the first pharmacological treatment for celiac disease — a condition currently managed exclusively through lifelong dietary gluten avoidance. The compound is being developed by 9 Meters Biopharma (formerly Innovate Biopharmaceuticals), which acquired the asset from Alba Therapeutics.
免責事項： この記事は情報提供および教育目的のみです。医療アドバイス、診断、治療を構成するものではありません。ペプチドの使用や健康関連のプロトコルについて決定を下す前に、必ず資格のある医療専門家にご相談ください。
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