Larazotide acetate is an investigational drug, classified as a synthetic eight-amino acid peptide. This compound is a tight junction regulator, designed to help restore the integrity of the intestinal barrier. It is being explored for its potential to address conditions where this barrier function is compromised.
How Larazotide Acetate Works
Larazotide acetate operates by targeting the tight junctions within the intestinal lining. These tight junctions are structures that control what passes between cells in the gut, ensuring that only necessary nutrients are absorbed and harmful substances are blocked. In certain conditions, these junctions can become “leaky,” allowing unwanted molecules to cross the intestinal barrier.
The drug acts as an antagonist of zonulin, a protein that can increase intestinal permeability. By blocking zonulin receptors, larazotide acetate prevents the disassembly of tight junctions, which are disrupted by stimuli like gluten peptides or bacterial antigens. This action helps maintain the intestinal barrier’s integrity, preventing the passage of inflammatory triggers. Larazotide acetate also inhibits myosin light chain kinase, an enzyme that influences the tension on actin filaments, promoting the closure of tight junctions.
Conditions Under Investigation
Larazotide acetate is primarily investigated for celiac disease. This autoimmune disorder is triggered by gluten ingestion, leading to damage in the small intestine. In individuals with celiac disease, gluten causes tight junctions to open, allowing gliadin, a component of gluten, to enter the space beneath the intestinal cells and provoke an immune response.
The rationale for using larazotide acetate in celiac disease is to reduce this “leaky gut” phenomenon. By keeping tight junctions closed, the drug prevents gliadin from crossing the intestinal barrier, mitigating the inflammatory reaction and associated symptoms. While a strict gluten-free diet is the standard management for celiac disease, many patients still experience persistent symptoms, and larazotide acetate is being explored as an adjunct therapy to improve their quality of life. Preclinical studies also explore larazotide acetate in other conditions involving intestinal barrier dysfunction, such as collagen-induced arthritis in mice and intestinal ischemic injury in pigs.
The Journey Through Clinical Trials
The development of larazotide acetate has progressed through various stages of clinical trials. Initial Phase 1 studies in healthy volunteers assessed its safety and tolerability. Doses from 0.25 mg to 36 mg showed a favorable safety profile. The drug was generally well-tolerated and did not cause severe drug-related side effects.
After Phase 1, larazotide acetate moved into Phase 2 trials involving celiac disease patients. These studies evaluated the drug’s efficacy and safety, often with a gluten challenge. Some Phase 2 trials indicated larazotide acetate could prevent gluten-induced symptoms and reduce inflammatory markers and intestinal permeability. For instance, one Phase 2b study with 342 adult celiac patients on a gluten-free diet found that a 0.5 mg dose significantly reduced symptoms.
Larazotide acetate advanced to Phase 3 clinical trials, large-scale studies designed to confirm effectiveness and safety before potential regulatory approval. The CeDLara trial, a Phase 3 study for celiac disease, aimed to assess larazotide acetate as an adjunct treatment for patients with persistent symptoms despite a gluten-free diet. However, an interim analysis in June 2022 led to the discontinuation of this Phase 3 trial. The number of additional patients needed for statistically significant results was deemed too large to continue feasibility. Despite this setback, collected data from the trial were planned for further analysis to explore potential benefits for other celiac disease symptoms, such as headache and fatigue.
Safety Considerations and Administration
Clinical trials of larazotide acetate reported a safety profile comparable to placebo. Common side effects include headaches and fatigue. Rare allergic reactions like skin rashes or itching are possible, as with any medication. Mild immune-related side effects have not been significant in trials.
Larazotide acetate is administered orally, as a capsule taken three times daily before meals. The drug acts locally within the gut, with minimal systemic absorption, primarily affecting intestinal epithelial cells. There is no clear relationship between drug dose and side effects; higher doses have not shown a greater incidence of adverse events. Larazotide acetate is not intended to replace a gluten-free diet but serves as an adjunctive therapy for managing symptoms.