Gastroenterology

Gastroenterology

Volume 146, Issue 7, June 2014, Pages 1649-1658
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac Disease

https://doi.org/10.1053/j.gastro.2014.02.031Get rights and content

Background & Aims

Gluten ingestion leads to small intestinal mucosal injury in patients with celiac disease, necessitating strict life-long exclusion of dietary gluten. Despite adherence to a gluten-free diet, many patients remain symptomatic and still have small intestinal inflammation. In this case, nondietary therapies are needed. We investigated the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial.

Methods

We established the optimal daily dose of gluten to be used in a 6-week challenge study. Then, in the intervention study, adults with biopsy-proven celiac disease were randomly assigned to groups given ALV003 (n = 20) or placebo (n = 21) together with the daily gluten challenge. Duodenal biopsies were collected at baseline and after gluten challenge. The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes were the primary end points.

Results

A daily dose of 2 g gluten was selected for the intervention study. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P = .0007; density of CD3+ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3+ intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P = .0133 and P = .0123, respectively). There were no statistically significant differences in symptoms between groups.

Conclusions

Based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten. Clinicaltrial.gov, Numbers: NCT00959114 and NCT01255696.

Section snippets

Gluten-Dose Optimization

To determine the optimal dose of gluten to be used in the interventional study, gluten challenges with 1.5 g, 3.0 g, or 6.0 g gluten (using breadcrumbs) were administered daily to adult celiac disease patients for 6 weeks (see Supplementary Material for gluten content assessment). Eligibility criteria included celiac disease diagnosis established by duodenal mucosal biopsy, attempted adherence to a GFD for 1 year or more, and being in clinical remission (ie, TG2-IgA−negative and reporting

Gluten-Dose Optimization

Before conducting the therapeutic intervention study, the optimal gluten-challenge dose was identified. Forty-seven patients were enrolled (Table 1) and assigned to 1 of 3 groups receiving a gluten challenge of 6.0 g (n = 17), 3.0 g (n = 15), or 1.5 g (n = 15) daily divided in 3 doses. The baseline mean VH:CrD values were similar in each group: 2.8, 2.6, and 2.8, respectively. All patients in the 6 g gluten/day group completed the study; 2 patients in the 3.0 g/day and 1 in the 1.5 g/day gluten

Discussion

Many celiac disease patients desire a novel nondietary alternative to the strict life-long GFD.14, 15, 35, 36 Despite long-term dietary gluten exclusion, small intestinal mucosal injury with crypt hyperplasia (Marsh grade II−III) is still present in 20%−80% of patients.12 In Finland, despite villus recovery in response to the GFD (96% with Marsh grade 0−I), persistent intraepithelial lymphocytosis is seen in more than half of patients studied.12 Small bowel mucosal healing is a prerequisite for

Acknowledgments

The authors are grateful to Robert N. Williams for the assistance with graphics design and statistical support.

Clinicaltrial.gov, ID: NCT00959114 and NCT01255696.

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    Conflicts of interest These authors disclose the following: Marja-Leena Lähdeaho is the principal investigator and is employed by FinnMedi Oy. Tiina Kärjä-Lahdensuu is an employee of FinnMedi Oy. Annette Marcantonio and Daniel C. Adelman are employees of Alvine Pharmaceuticals, Inc. Markku Mäki is a scientific advisor to Alvine Pharmaceuticals, Inc., ImmusanT, Inc, BioLineRx, Ltd, and Flamentera, AG. The remaining authors disclose no conflicts.

    Funding This study was sponsored by Alvine Pharmaceuticals, Inc., San Carlos, CA. Celiac Disease Study Group (M.-L.L., K.K., K.L., and M.M.) received financial supported by the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (Grants 9R034 and 9R018), Academy of Finland, and The Sigrid Juselius Foundation.

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