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Larazotide

Also known as larazotide acetate, AT-1001, INN-202, FZI/0

Oral octapeptide that closes tight junctions in the gut; phase 3 in coeliac disease halted for futility.

early-clinical Recovery & tissue research chemical

At a glance

Category
Recovery & tissue
Status
research chemical
Route
oral, delayed release; acts locally in the intestinal lumen
Half-life
Cannot be determined: in human studies plasma concentrations at all doses tested remained below the limit of quantification of 0.5 ng/ml. There is no meaningful systemic half-life, and a porcine study of the delayed-release form found luminal peak concentrations of 0.32-1.76 microMolar in the distal duodenum and proximal jejunum without systemic uptake 4
Onset
in the studies measurement was over 12 weeks
Molecular weight
725.9 g/mol (free peptide); supplied as the acetate salt
Sequence
GGVLVQPG (Gly-Gly-Val-Leu-Val-Gln-Pro-Gly)

Not approved, in any country. Received Fast Track status from the FDA for coeliac disease as an adjunct to the gluten-free diet in patients with persistent symptoms. Development stalled after the phase 3 study, CeDLara (NCT03569007), was terminated by the sponsor with a completion date of 21 July 2022 5.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Larazotide is an antagonist of the zonulin pathway. It binds competitively to the zonulin receptor on the luminal side of the intestinal epithelium and thereby prevents tight junctions from coming apart.

In addition, inhibition of myosin light chain kinase has been described, which reduces actomyosin tension in the cell and closes the tight junction.

The net effect is reduced paracellular permeability and therefore less passage of gliadin peptides from the lumen into the lamina propria. In coeliac disease that is the intended protective step.

The drug acts exclusively from the luminal side; the delayed-release form targets the mid duodenum and the proximal jejunum. Systemic uptake is negligible, which explains why no usable pharmacokinetics can be measured.

What the research shows

Of the peptides in this category, larazotide has advanced furthest in clinical development: several randomised, placebo-controlled studies were carried out up to and including phase 3. The outcome, however, is negative. One medium-sized phase 2b study was positive at one dose, but that finding was not confirmed in phase 3.

Research in humans

The phase 2b study (Gastroenterology, 2015) enrolled 342 adults with coeliac disease who had persistent symptoms despite at least twelve months of a gluten-free diet 1. Only 0.5 mg three times daily met the primary endpoint (CeD-GSRS score; p=0.022) 1. The higher doses of 1 and 2 mg did not — an inverse dose-response relationship 1. Secondarily, an approximately 26% reduction in symptomatic days on the CeD-PRO was seen 1. The subsequent phase 3 study CeDLara (NCT03569007, sponsor 9 Meters Biopharma, started under Innovate Biopharmaceuticals) randomised approximately 525 patients to 0.25 mg, 0.5 mg or placebo three times daily, with the change in the abdominal domain of the CeD-PRO over 12 weeks as the primary endpoint 5. In June 2022 a pre-planned futility analysis concluded that the number of participants required to still demonstrate a significant difference from placebo was not attainable; the study was stopped 5. It was a matter of futility, not a safety signal. An earlier gluten challenge study (n=86) was inconclusive because the permeability endpoint proved too variable in outpatients.

Animal and lab research

In ischaemically damaged porcine jejunum, larazotide accelerated the recovery of barrier function at approximately 1 microMolar. A porcine study with the delayed-release form confirmed luminal peak concentrations of 0.32 to 1.76 microMolar in the distal duodenum and proximal jejunum, without systemic uptake 4. In rodents, larazotide prevented zonulin-induced barrier dysfunction.

Caveats. The picture is that of one positive medium-sized study that was not replicated in a larger, adequately designed phase 3 study. The inverse dose-response relationship in phase 2b was in itself already a reason for caution. In the gluten challenge study the lactulose-mannitol permeability test proved too variable to serve as an endpoint. There is no approved formulation, and therefore no package leaflet or established contraindications.

What it is used for

  • Coeliac disease with persistent symptoms despite a gluten-free diet - studied to phase 3 and not proven effective; the phase 2b met its primary endpoint only at 0.5 mg three times daily 1 and the phase 3 was terminated by the sponsor 5
  • Used outside study settings in practice for intestinal permeability ('leaky gut'), an indication for which no clinical evidence exists

Dosing

Dose
0.25 mg or 0.5 mg per intake, three times daily, in the phase 2b and phase 3 coeliac disease trials
Frequency
3x daily
Route
oral, 15 minutes before the meal
Duration
12 weeks in the studies, with a 12-week extension for safety in phase 3
  • Only 0.5 mg three times daily met the primary endpoint in phase 2b (p=0.022); the 1 mg and 2 mg arms did not 1. More is demonstrably not better here.
  • Separately from the therapeutic dose: phase 1 tolerability work in healthy volunteers went up to single and multiple oral doses of 36 mg without severe drug-related effects, and plasma concentrations stayed below the 0.5 ng/ml limit of quantification throughout. That 36 mg is a safety ceiling from a different study population, not a dose anyone proposed for treatment, and it is roughly seventy times the dose that worked.
  • Intake shortly before the meal is essential for the intended local mechanism of action: the drug acts from the luminal side on tight junctions and must arrive ahead of the gluten 3.
  • The drug is not approved and not legally available as a medicine; the doses mentioned are study doses, not advice.
  • A separate practice, captured in the section below, has grown up outside coeliac disease entirely: a 'leaky gut' and ME/CFS community that takes the same trial dose for an indication that has never been studied.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Phase 2b trial in coeliac disease with persistent symptoms

published trial

Source: Gastroenterology, 2015

Weeks 1-12, effective arm0.5 mg three times daily, orally, 15 minutes before each meal
Weeks 1-12, higher-dose armshigher doses were tested in the same trial and did not separate from placebo
Extensiona further 12 weeks was run for safety in phase 3

The dose-response runs backwards, which is the most informative thing about this schedule: only the lowest arm beat placebo. The timing is not a convenience instruction — the mechanism is local tight-junction regulation in the lumen, so the dose has to arrive ahead of the gluten. The drug is approved nowhere; these are study doses.

'Leaky gut' self-dosing pattern for unstudied indications (circulating)

user protocol — not validated

Source: Chronic-illness and biohacker forums and grey-market vendors selling capsules

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Reported dose0.25-0.5 mg (250-500 mcg) three times daily, taken orally before meals
Reported productgrey-market capsules, commonly labelled 250 mcg; some users buy raw powder and fill their own capsules
Reported userun for weeks to months for 'intestinal permeability', ME/CFS, food sensitivities and general gut complaints

This copies the coeliac trial's 0.5 mg three-times-daily figure and applies it to indications that were never studied: there is no trial of larazotide for 'leaky gut', ME/CFS or non-coeliac gut complaints, and the one indication it was actually developed for produced a phase 3 that was stopped for futility 5. The trial finding that only the lowest arm beat placebo, with higher doses failing 1, sits directly against the usual 'more is better' instinct, so users self-escalating are moving away from the one dose that ever separated from placebo. Grey-market capsules are of unverified identity and potency, and people who self-fill from bulk powder are measuring sub-milligram amounts on scales not built for it. There is no systemic exposure to point to any pharmacological harm, but equally none of the claimed benefit outside coeliac disease has any evidence behind it.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Safety

Side effects

  • In phase 2b tolerability was comparable to placebo at all doses 1
  • Gastrointestinal complaints were the most frequently reported side effects, distributed equally across the treatment and placebo groups 1
  • In the gluten challenge study, headache and urinary tract infection were the most frequently reported side effects 2
  • Mild headache was the most common complaint in phase 1
  • No drug-related serious side effects; no relevant changes in vital signs, laboratory values or ECG

Do not use if

  • There are no established contraindications, because the drug was never approved and therefore no package leaflet exists
  • Pregnancy and breastfeeding: not studied
  • Larazotide does not replace the gluten-free diet and has been studied solely as an adjunct to it in patients with persistent symptoms despite at least twelve months of the diet 1

Interactions

Not systematically studied. Because there is no measurable systemic exposure, systemic interactions are considered unlikely. That is a line of reasoning, not an established fact.

Sources