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Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: a Randomized Controlled Trial Daniel A

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Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: a Randomized Controlled Trial Daniel A Gastroenterology 2015;148:1311–1319 CLINICAL—ALIMENTARY TRACT Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: A Randomized Controlled Trial Daniel A. Leffler,1 Ciaran P. Kelly,1 Peter H. R. Green,2 Richard N. Fedorak,3 Anthony DiMarino,4 Wendy Perrow,5 Henrik Rasmussen,5 Chao Wang,5 Premysl Bercik,6 Natalie M. Bachir,7 and Joseph A. Murray8 1The Celiac Center at Beth Israel Deaconess Medical Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2Celiac Disease Center at Columbia University, New York, New York; 3Center of Excellence for Gastrointestinal Immunity and Inflammation Research, University of Alberta, Edmonton, Alberta, Canada; 4Thomas Jefferson CLINICAL AT University, Philadelphia, Pennsylvania; 5Alba Therapeutics Corporation, Baltimore, Maryland; 6McMaster University, Hamilton, Ontario, Canada; 7Essentia Health Duluth Clinic, Duluth, Minnesota; 8Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota BACKGROUND & AIMS: Celiac disease (CeD) is a prevalent symptoms may have a variety of causes, one potential autoimmune condition. Recurrent signs and symptoms are source is sporadic gluten exposure,7 which may contribute common despite treatment with a gluten-free diet (GFD), yet no to persistent enteropathy, continued symptoms, and approved or proven nondietary treatment is available. reduced quality of life. METHODS: In this multicenter, randomized, double-blind, In CeD, paracellular permeability is increased by an in- placebo-controlled study, we assessed larazotide acetate 0.5, flammatory response to gluten entry into the intestinal mu- 1, or 2 mg 3 times daily to relieve ongoing symptoms in 342 cosa.8 Increased permeability promotes gluten peptide adults with CeD who had been on a GFD for 12 months or transport to gut-associated lymphoid tissue, initiating inflam- – longer and maintained their current GFD during the study. The matory cytokine release and T-cell recruitment.8 10 An intes- study included a 4-week placebo run-in, 12 weeks of treatment, tinal permeability–inflammation loop is established, leading to and a 4-week placebo run-out phase. The primary end point a multitude of gastrointestinal and systemic manifestations.11 was the difference in average on-treatment Celiac Disease Larazotide acetate is a novel, locally acting, nonsystemic, Gastrointestinal Symptom Rating Scale score. RESULTS: The – primary end point was met with the 0.5-mg dose of larazotide synthetic, 8 amino acid oral peptide, discovered during – acetate, with fewer symptoms compared with placebo by functional screening of synthetic Vibrio cholera related fi modified intention to treat (n ¼ 340) (analysis of covariance, peptides. Larazotide acetate is a rst-in-class tight junction P ¼ .022; mixed model for repeated measures, P ¼ .005). The (TJ) regulator under development as an adjunct to a GFD. 0.5-mg dose showed an effect on exploratory end points Larazotide acetate appears to prevent opening of intestinal including a 26% decrease in celiac disease patient-reported TJs by promoting TJ assembly and actin filament rear- outcome symptomatic days (P ¼ .017), a 31% increase in rangement, which prevents gluten from reaching the intes- improved symptom days (P ¼ .034), a 50% or more reduction tinal submucosa and triggering an inflammatory response from baseline of the weekly average abdominal pain score for 6 (Supplementary Figure 2).8,12 or more of 12 weeks of treatment (P ¼ .022), and a decrease in Nonclinical studies with larazotide acetate have shown the nongastrointestinal symptoms of headache and tiredness proof-of-concept of TJ regulation including the inhibition of (P ¼ .010). The 1- and 2-mg doses were no different than gliadin-induced TJ alteration, macrophage recruitment, and placebo for any end point. Safety was comparable with placebo. increases in intestinal permeability.8,12,13 In 4 prior clinical CONCLUSIONS: Larazotide acetate 0.5 mg reduced signs and trials, larazotide acetate showed a safety profile comparable symptoms in CeD patients on a GFD better than a GFD alone. with placebo.14–16 In initial clinical trials using gluten Although results were mixed, this study was a successful trial of challenge, larazotide acetate prevented gluten-induced a novel therapeutic agent targeting tight junction regulation in symptoms and blunted increases in anti-tissue trans- patients with CeD who are symptomatic despite a GFD. glutaminase (tTG) antibodies, interferon-g, and intestinal Clinicaltrials.gov: NCT01396213. permeability.14–16 These results provided the foundation for the current phase IIb study. Keywords: Celiac Disease; Gluten; Therapeutic; Tight Junction. Abbreviations used in this paper: ANCOVA, analysis of covariance; BMI, eliac disease (CeD), a genetic autoimmune condition, body mass index; CeD, celiac disease; CeD-GSRS, Celiac Disease C affects approximately 1% of the Western popula- Gastrointestinal Symptom Rating Scale; CeD PRO, Celiac Disease 1,2 Patient-Reported Outcome; DGP, deamidated gliadin peptide; GFD, tion. CeD is triggered by ingestion of gluten-containing gluten-free diet; GI, gastrointestinal; MMRM, mixed model for repeated foods and managed by a gluten-free diet (GFD).3,4 Recur- measures; TJ, tight junction; tTG, tissue transglutaminase. rent CeD signs and symptoms resulting from inadvertent or deliberate gluten exposure have been reported in approxi- © 2015 by the AGA Institute 5,6 0016-5085/$36.00 mately 70% of CeD patients on a GFD. Although persistent http://dx.doi.org/10.1053/j.gastro.2015.02.008 1312 Leffler et al Gastroenterology Vol. 148, No. 7 Despite being a common condition that often responds performed centrally using the INOVA (San Diego, CA) Quanta- incompletely to GFD, there is currently no approved non- Flash assay at Mayo Clinical Laboratories. The cut-off value for dietary treatment for CeD.17,18 This multicenter, randomized, levels that were positive for tTG IgA and IgG were 4.0 and 6.0, placebo-controlled trial was a large clinical trial conducted in respectively. The cut-off value for levels that were for positive CeD patients and was designed to assess the efficacy and deamidated gliadin peptide (DGP) IgA and IgG were 20. To safety of larazotide acetate as an adjunct to a GFD in adult evaluate study-related changes in serologic titers, patients with patients with persistent symptoms despite maintenance of a undetectable anti-tTG and anti-DGP antibody levels were long-term GFD. A secondary objective was to validate the excluded. Patients experienced at least 1 gluten-related symp- Celiac Disease Patient-Reported Outcome (CeD PRO) instru- tom (diarrhea, abdominal pain, bloating, nausea) in the month ment as a daily measure of therapeutic effects. before screening, and at screening were required to have a qualifying score of 2 or higher, reflecting “mild discomfort” on CLINICAL AT the CeD domains of the Gastrointestinal Symptom Rating Scale19 Materials and Methods (CeD-GSRS). The GSRS and CeD-GSRS, which contains 10 items The protocol was approved by relevant institutional review from the GSRS, diarrhea, abdominal pain, and indigestion do- mains (Supplementary Appendix A), have been used in multiple boards. Patients provided written informed consent, the study – trials of CeD14,20 22 and other gastrointestinal (GI) disor- was conducted according to Good Clinical Practice, and was 23,24 registered on Clinicaltrials.gov (NCT01396213). ders. All survey data were collected daily from patients us- ing an electronic clinical outcome assessment data collection device (Bracket Global, Wayne, PA). Patients Exclusion criteria included refractory CeD, severe CeD com- Entry criteria were as follows: age 18–75 years, body mass plications (eg, enteropathy-associated T-cell lymphoma), other index (BMI) of 16–45 kg/m2, CeD confirmed by intestinal biopsy chronic inflammatory GI disease (eg,inflammatory bowel disease), or capsule endoscopy (capsule endoscopy was the entry criteria diabetes, or autoimmune, psychiatric, or neurologic disease that for 7 of 342 patients randomized) plus positive serology 12 could interfere with assessments. Smoking, pregnancy or breast- months before study entry, maintenance of a GFD for 12 or more feeding, previous exposure to larazotide acetate, concomitant use consecutive months before screening, and adherence to current of systemic or intestinal immune suppressants, continuous anti- GFD on study. Underweight patients (BMI, 16–18.5 kg/m2) were biotics, nonsteroidal anti-inflammatory drugs, and medications included because these patients were believed by the in- that alter gastric pH or intestinal permeability were prohibited. vestigators to reflect patients who were underweight as a result of active celiac disease and thus would be most likely to benefit from therapy underweight due to active celiac disease and thus Study Design and Procedures would be likely to benefit from therapy while not at increased This 20-week study was conducted in 3 phases: a 4-week risk of complications of severe malabsorption owing to severe single-blind placebo run-in phase, a 12-week double-blind malabsorption or other conditions. All celiac serologies were treatment phase, and a 4-week placebo run-out phase Figure 1. Primary end point: average on-treatment scores on the CeD-GSRS. The 0.5-mg larazotide acetate dose met the primary end point. June 2015 Larazotide Acetate in Celiac Disease 1313 (Figure 1). A qualifying score of 2 or higher on the CeD-GSRS laboratory parameters (hematology, chemistry,
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