Larazotide acetate is a novel oral drug candidate investigated for treating Celiac Disease by addressing intestinal barrier dysfunction. This synthetic medication was designed to repair the integrity of the intestinal lining, which is often compromised in Celiac Disease patients. It was intended to be the first pharmacological treatment used alongside the standard gluten-free diet.
The Role of Zonulin and Gut Permeability
The lining of the small intestine acts as a barrier, controlling what substances pass from the gut lumen into the bloodstream. This barrier is formed by a single layer of cells sealed by structures known as tight junctions. These junctions are dynamic gates that open and close to allow nutrient absorption while blocking the passage of larger, potentially harmful molecules.
Zonulin is the primary biological regulator of these tight junctions, signaling them to open. In Celiac Disease, exposure to gluten peptides triggers the over-release of zonulin in genetically susceptible individuals. This excessive zonulin signals the tight junctions to loosen, resulting in increased intestinal permeability, often called a “leaky gut.”
When tight junctions open, large molecules like undigested gluten peptides pass through the intestinal wall. This allows gluten fragments to reach the underlying immune tissue, which identifies them as a threat. The resulting immune response leads to the chronic inflammation and damage that characterizes Celiac Disease.
How Larazotide Acetate Restores Barrier Function
Larazotide acetate is a synthetic eight-amino acid peptide that acts as a targeted inhibitor of zonulin. The drug restores intestinal barrier function by preventing zonulin from disrupting the tight junctions. Larazotide acetate is administered orally and works directly within the gastrointestinal tract without significant absorption into the bloodstream.
The peptide functions as a zonulin antagonist by competitively binding to zonulin receptors on the surface of intestinal lining cells, including the Epidermal Growth Factor Receptor (EGFR) and Protease-Activated Receptor 2 (PAR2). By occupying these sites, Larazotide acetate prevents zonulin from binding and initiating the signaling cascade that causes the tight junctions to separate.
This blockade keeps the tight junctions in their closed state, significantly reducing the “leakiness” of the gut barrier. By keeping the intestinal wall intact, the drug limits the amount of gluten peptides that cross into the submucosa and trigger the immune reaction. This reduction mitigates symptoms and intestinal damage associated with accidental gluten exposure.
Clinical Trial Progress and Results
Larazotide acetate was the first Celiac Disease treatment to reach Phase 3 trials. Earlier Phase 2 studies, involving patients undergoing a controlled gluten challenge, showed the drug was well-tolerated and significantly reduced gastrointestinal symptoms compared to a placebo. These positive results led the FDA to grant the drug a Fast Track designation, intended to expedite the review of treatments for serious conditions.
The company 9 Meters Biopharma initiated the pivotal Phase 3 trial, known as CedLara. This large-scale, placebo-controlled study aimed to confirm the drug’s efficacy and safety in Celiac Disease patients who still experienced symptoms despite adhering to a gluten-free diet. The primary goal was to show a clear reduction in symptoms, measured by a validated patient-reported outcome scale.
Despite promising Phase 2 data, 9 Meters Biopharma discontinued the CedLara trial in June 2022. An interim analysis determined the drug was not showing a statistically significant clinical effect on the primary endpoint. The analysis indicated that continuing the trial to potentially demonstrate efficacy was not feasible, leading the company to halt the study.
Potential Impact on Celiac Disease Management
Had larazotide acetate proven successful, it would have represented a profound shift in Celiac Disease management. It was positioned as the first non-dietary therapeutic option, offering protection against unintentional gluten ingestion. The drug was intended to be taken orally before meals, acting as a safeguard against the immune-triggering effects of cross-contamination.
The primary benefit would have been improved patient quality of life, offering peace of mind to those facing anxiety about hidden gluten. For patients with persistent symptoms despite a strict gluten-free diet, a drug that sealed the gut barrier could have provided substantial symptomatic relief. Although the Phase 3 trial failed, the research established a scientific groundwork for future drug candidates targeting the intestinal barrier.