Larazotide vs B7-33.

Larazotide (larazotide acetate, research code AT-1001) is a synthetic eight-amino-acid peptide investigated as an oral, gut-restricted therapy for celiac disease. It was designed to act locally in the small intestine rather than being absorbed systemically. The concept was to add a first non-dietary treatment for patients who still have symptoms despite a gluten-free diet. It advanced through Phase 2 and into Phase 3 development but is not approved by the FDA or any major regulator. It is categorized under healing because its target is intestinal barrier repair and integrity.

B7-33 is an experimental single-chain peptide derived from the B-chain of the human hormone relaxin-2 (H2 relaxin). Native relaxin is a complex two-chain molecule linked by disulfide bonds and is difficult and costly to manufacture; B7-33 is a simplified 24-amino-acid single-chain mimetic intended to keep the useful anti-fibrotic activity while being easier to make. It is a laboratory research compound only, studied in cells and animals for fibrosis of the heart, kidney, lung, and blood vessels. It has never been tested in humans and has no approved use. It is categorized under healing because its studied effects are anti-fibrotic and tissue-remodeling.

Larazotide is a tight-junction regulator, often described as a zonulin antagonist. In celiac disease, gluten exposure is associated with increased release of zonulin and loosening of the tight junctions between intestinal epithelial cells, allowing gluten peptides to cross the barrier and drive immune activation. Larazotide is proposed to promote tight-junction assembly and reduce paracellular permeability (leaky gut), thereby limiting gluten peptide entry and downstream inflammation. It is intended to work in the gut lumen, which fits its minimal systemic absorption. The precise molecular target and the physiological role of zonulin itself remain areas of scientific debate.

B7-33 is a functionally selective (biased) agonist of the relaxin family peptide receptor 1 (RXFP1). Rather than strongly activating the cAMP pathway like native relaxin, it preferentially signals through the pERK pathway at RXFP1. This biased signaling is proposed to drive anti-fibrotic effects, notably increased activity of matrix-degrading enzymes such as MMP-2, which break down excess collagen, while potentially avoiding some effects tied to broader relaxin signaling. In preclinical models it has shown vasoprotective and cardioprotective actions consistent with relaxin biology. The single-chain design is meant to preserve receptor engagement without the manufacturing burden of the two-chain hormone.

Mid-stage data were encouraging but the definitive trial did not succeed. In a Phase 2b randomized, double-blind, placebo-controlled trial (Leffler et al., Gastroenterology, 2015; 342 patients with persistent symptoms despite a gluten-free diet), low-dose larazotide reduced patient-reported symptoms versus placebo, with the lowest dose showing the clearest signal. On the strength of such results the program advanced to a large Phase 3 trial (CeD-2001) run by 9 Meters Biopharma. That Phase 3 study was halted after an interim analysis indicated it was unlikely to meet its primary endpoint, the change from baseline in celiac symptom severity, effectively ending the program. In short: positive Phase 2b data did not translate into a successful Phase 3 result, and larazotide is not an approved therapy. Several features of the earlier evidence look different in hindsight. The Phase 2b result was strongest at the lowest dose tested, without a conventional dose-response relationship, a pattern that is difficult to interpret mechanistically and that often does not reproduce. Primary endpoints across the program were patient-reported symptom scores rather than histology or objective mucosal healing, and symptom scores in celiac disease are noisy and prone to large placebo responses. Supporting biology exists outside these trials: larazotide acetate promoted recovery of ischemia-injured porcine jejunum through repair of tight junctions (PLoS One, 2021), and reviews of celiac pharmacotherapy place tight-junction regulation among several strategies that have been tried without yet producing an approved drug (European Journal of Pharmacology, 2021). The comparison that matters is with existing management. A strict lifelong gluten-free diet remains the only established treatment for celiac disease, supported by decades of clinical experience and by histologic and serologic recovery in patients who adhere to it. No drug has been approved as an adjunct or replacement. Larazotide reached the last stage of testing and failed there, so the honest summary is that the leading non-dietary candidate did not demonstrate benefit when tested at confirmatory scale.

All evidence is preclinical: cell-culture and animal studies, with no clinical trials. B7-33 has never been administered to a human being in a registered study, so no efficacy or safety claim about people can be drawn from the literature that exists. The founding paper (Hossain et al., Chemical Science, 2016) described the design of B7-33 and showed it binds RXFP1 and preferentially activates pERK over cAMP, with anti-fibrotic activity in cell and animal models of heart, lung, and kidney fibrosis. That work combined receptor pharmacology in transfected cell lines with short rodent experiments, using tissue collagen content and enzyme activity as endpoints, in small groups, without the randomization and blinding conventions that govern clinical research. Subsequent work reported vascular and cardiac benefits, including a study finding that B7-33 maintained relaxin's cardioprotective effects and reduced left-ventricular fibrosis more rapidly than the ACE inhibitor perindopril in an experimental model of cardiomyopathy (Alam et al., Biomedicine and Pharmacotherapy, 2023). Additional reports describe effects in myocardial-infarction remodeling and in hypertrophic-scar fibroblasts in vitro. These are early-stage animal and laboratory findings; no human efficacy or safety has been demonstrated, and translation to people is unproven. The cautionary comparison is the parent molecule. Serelaxin, recombinant human relaxin-2, travelled the whole distance: it produced encouraging earlier-phase signals in acute heart failure, then failed to improve clinical outcomes in the large RELAX-AHF-2 trial, and analyses of that dataset have continued to examine why its biomarker and end-organ signals did not convert into patient benefit. A biased RXFP1 agonist that performs well in rodent fibrosis models is therefore starting from a class whose flagship compound already failed a definitive human outcome trial. For B7-33 itself there is no human pharmacokinetic data, no dose-finding work, no formal toxicology package, no immunogenicity assessment, and no registered clinical trial.

Across trials larazotide was generally well tolerated, consistent with a peptide that acts locally in the gut and is minimally absorbed. Reported adverse events were typically mild and gastrointestinal, such as abdominal discomfort, nausea, or headache, and were often similar between drug and placebo groups. Minimal systemic absorption limits the plausibility of effects outside the intestinal lumen, and no distinctive organ toxicity emerged as a program-stopping signal; the Phase 3 trial was discontinued for likely futility on efficacy, not for safety. Because development stopped before approval, there is no long-term real-world safety dataset in a broad treated population. Clinical trial exposure was limited in duration and confined to selected participants who met entry criteria, so effects of use over years, in children, in pregnancy, in older patients with comorbidities, or alongside common medications were never characterized. There is no post-marketing pharmacovigilance stream because there is no marketed product, and no regulator has reviewed a complete safety dossier. Anything sold as larazotide outside a clinical trial carries the separate risks of unapproved supply: no verified identity or purity, no batch testing, no good manufacturing practice oversight, and no adverse-event reporting. There is also an indirect risk specific to celiac disease, since any product presented as protection against gluten exposure could encourage relaxation of the gluten-free diet, which remains the only established management and the only intervention shown to allow mucosal recovery. This entry is educational only and is not a recommendation to obtain or use the compound, which is not an approved medicine.

There are no human safety data for B7-33 because it has not entered clinical trials; all information comes from cell and animal experiments. Preclinical reports have not flagged prominent toxicities in the models studied, but absence of reported harm in a handful of animal studies is not evidence of human safety. Those studies were small, short, and designed to detect efficacy signals rather than toxicity, and none included the systematic histopathology, reproductive testing, or repeat-administration escalation that regulators require before a first human exposure. Relaxin biology indicates where problems would be looked for. Relaxin is a vasodilator and a systemic tissue-remodeling hormone, so blood pressure effects, renal hemodynamic changes, and unwanted matrix degradation in tissues that were not the target are the plausible concerns for any RXFP1 agonist. The anti-fibrotic mechanism that is desirable in a scarred heart is not obviously desirable everywhere else in the body. Clinical experience with serelaxin showed that an RXFP1 agonist can be given to acutely ill patients without an alarming adverse-event profile, but serelaxin is a different molecule with different signaling bias and different pharmacokinetics, and that experience does not transfer to a single-chain mimetic. Purity, dosing, and long-term effects in humans are entirely unknown, and immunogenicity against a synthetic single-chain sequence has never been assessed. Products marketed online as B7-33 are research chemicals, not medicines, and are not intended for human use, with no verified identity, sterility, or endotoxin testing behind them. This entry is educational only and does not provide any usage guidance.

Larazotide is investigational and is not approved by the FDA or EMA for celiac disease or any other indication. It reached Phase 3, but the pivotal CeD-2001 trial was discontinued for likely futility on its primary endpoint. Any product sold as larazotide outside of a clinical trial is not an approved drug.

B7-33 is a preclinical research compound with no FDA or other regulatory approval and no approved indication. It has not been evaluated in human clinical trials. It is sold, where sold, only as a research reagent labeled not for human consumption.