Larazotide

Also known as: AT-1001, INN-202

Evidence: Clinical

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Overview

Synthetic octapeptide (AT-1001) that blocks zonulin-mediated opening of intestinal tight junctions; tested in human celiac disease trials as an adjunct to a gluten-free diet.

Larazotide acetate (AT-1001) is an oral eight-residue peptide developed by Alba Therapeutics and later 9 Meters Biopharma as an add-on to a gluten-free diet in celiac disease. Four randomized placebo-controlled trials have been published. In gluten-challenge studies (2.4 to 2.7 g gluten/day) it limited symptom worsening and blunted the rise in anti-transglutaminase IgA, but never separated from placebo on the lactulose/mannitol permeability ratio (Leffler 2012, n=86; Kelly 2013, n=184). A 12-week phase 2b trial in 342 adults already on a gluten-free diet met its symptom endpoint at 0.5 mg three times daily, while 1 and 2 mg did not (Leffler 2015). The phase 3 trial (NCT03569007, n=307) was terminated by the sponsor. Nothing is approved; a 2022 meta-analysis of the four RCTs found symptom benefit only in gluten-challenge subgroups.

Benefits

Reduced gluten-induced symptoms in celiac disease (human RCTs), reduced rise in anti-tTG IgA during gluten challenge (human RCT), tight-junction protection in Caco-2 cells and gliadin-sensitized mice; no effect on measured intestinal permeability in any trial

Dosing reference

Research dose: 0.25 to 2 mg orally three times daily in trials; only 0.5 mg three times daily met a primary endpoint (n=342)
Range: 250 to 2000 mcg, 3x daily

Oral capsule, taken before meals, studied only as an add-on to a continued gluten-free diet. The dose response is inverse: 0.5 mg three times daily beat placebo on symptoms while 1 and 2 mg did not, and in the gluten-challenge study 1 mg worked where 8 mg did not.

Mechanism

Larazotide acetate is an octapeptide (GGVLVQPG) that acts in the gut lumen to keep epithelial tight junctions closed. In Caco-2 and IEC6 monolayers it blocked the ZO-1 and actin redistribution caused by gliadin fragments, by the zonula occludens toxin-derived peptide AT-1002 and by basolateral cytokines, prevented the fall in transepithelial electrical resistance, and reduced translocation of an immunogenic gliadin 13-mer; in gliadin-sensitized HLA-HCD4/DQ8 mice it preserved tight-junction structure and reduced intestinal macrophage accumulation (Gopalakrishnan 2012). It is usually described as a zonulin antagonist, but no binding study to a zonulin receptor has been published, so the receptor-level mechanism is proposed rather than shown. Human trials found no change in the lactulose/mannitol permeability ratio at any dose.

Evidence

Clinical: at least one published human trial or an approved drug

In 86 diet-controlled celiac patients given 2.4 g gluten/day for 14 days, larazotide 0.25 to 8 mg TID did not change the lactulose/mannitol ratio, but lower doses limited the gluten-induced rise in symptom scores (Leffler et al., 2012)
In 184 patients on a 6-week gluten challenge (2.7 g/day), 1 mg TID limited symptoms (p=0.002) and anti-tTG IgA rose 5.8-fold vs 19.0-fold on placebo (p=0.010); the permeability endpoint was again negative (Kelly et al., 2013)
In 342 adults symptomatic despite 12+ months of a gluten-free diet, 0.5 mg TID beat placebo on the celiac GI symptom score over 12 weeks (p=0.022); 1 and 2 mg did not differ from placebo (Leffler et al., 2015)
In Caco-2 cells and gliadin-sensitized transgenic mice it preserved tight-junction structure and blocked gliadin-induced permeability (Gopalakrishnan et al., 2012)
A meta-analysis of the four RCTs (626 patients) found symptom improvement only in the gluten-challenge subgroup and no permeability effect (Hoilat et al., 2022)
Human-trial status: four published phase 2 RCTs; the phase 3 trial (NCT03569007, n=307) was terminated by the sponsor and no regulator has approved it

References

Side effects

Well tolerated in celiac trials, with headache, nausea, and abdominal discomfort reported at rates near placebo, since it acts locally in the gut with minimal systemic absorption. Urinary tract infection and flatulence were also noted in trials. It is not a substitute for a gluten-free diet.

Storage

Storage: Room temperature
Lyophilized: 24+ months

Pharmacology

Half-life: No published human plasma t½; acts in the gut lumen with minimal systemic absorption (oral)
Bioavailability: Oral: Designed for local GI action, minimal systemic absorption
Molecular weight: 725.8 Da
Sequence: GGVLVQPG