Larazotide

A synthetic octapeptide derived from the C-terminal region of zonula occludens toxin (ZOT) from Vibrio cholerae. Larazotide competitively blocks zonulin receptors on intestinal epithelial cells, preventing tight junction disassembly and reducing paracellular permeability. It acts entirely within the intestinal lumen with zero systemic absorption — a property so definitive that the FDA granted a thorough QT study waiver.

Larazotide was the most advanced investigational therapeutic for celiac disease, progressing through Phase 1, 2a, 2b, and into Phase 3 before the CedLara trial was discontinued for futility in June 2022. The Phase 2b trial was the first novel celiac disease agent trial to meet its primary endpoint. Development has been halted by 9 Meters Biopharma.

Larazotide progressed through an unusually complete clinical development program before Phase 3 futility. The Phase 1 proof-of-concept (N=21) showed AT-1001 completely blocked gluten-induced intestinal permeability increases. The pivotal Phase 2b trial (N=342) was the largest celiac disease RCT at the time and the first novel celiac agent to meet its primary endpoint, though only the 0.5 mg TID dose achieved significance (P=0.022) — higher doses (1 mg, 2 mg) did not, producing a bell-shaped dose-response curve attributed to brush border aminopeptidase M degradation generating inhibitory fragments.

The Phase 3 CedLara trial tested 0.25 mg and 0.5 mg TID but was discontinued for futility at interim analysis in June 2022. Separately, larazotide showed promise in a small case series for MIS-C, and trials for Long COVID gut permeability have been explored. No successor program with modified analogs has been publicly announced.