The Gluten Free Diet and Potential Alternative Therapies: The Road Ahead Daniel Leffler MD, MS Associate Professor of Medicine Harvard Medical School HARVARD MEDICAL SCHOOL
Let Thy Food Be Thy Medicine Hippocrates, 400 AD Strict gluten free diet is the only accepted treatment for celiac disease The GFD is one of the more challenging treatments we assign patients GFD
Patient Satisfaction with the GFD is Low Controversial in the past Better scientific data and a more diverse celiac population general acceptance Sanders JGLD 2011
Treatment Burden is also Second Only to Hemodialysis 0 20 40 60 80 100 Perceived Treatment Burden VAS* CD HTN GERD ESRD DM CHF IBD IBS *VAS: 0=Very Easy 100=Very Difficult Shah S, Leffler DA, AJG 2014
Spectrum of NRCD in Children and Adults Other 8% IBS 18% Gluten Exposure 35% RCD 11% SIBO 6% Eating Disorder 6% Disacchari dase Deficiency 9% Microsco pic Colitis 7% Leffler et al, CGH 2007; Veeraraghavan ACG 2015
Spectrum of NRCD in Children and Adults Other 8% IBS 18% Gluten Exposure 35% RCD 11% SIBO 6% Eating Disorder 6% Disacchari dase Deficiency 9% Microsco pic Colitis 7% Leffler et al, CGH 2007; Veeraraghavan ACG 2015
Histologic Recovery is Partial and Age Related Average Age of Celiac Diagnosis l/3 of people have a healthy intestine after 2 years 2/3 of people have a healthy intestine after 5 years Lebwohl et al. APT 2014, Rubio-Tapia AJG 2010, Leffler DA Gut 2012, Maki Gastro 2014
Three Main Therapeutic Classes Class Examples Intraluminal Therapies ALV003: oral protease combination of cysteine endoprotease B-soform 2 and prolyl endopeptidase Lazarotide Acetate: 8 polymer peptide and tight junction regulator KumaMax: Synthetic oral protease BL-7010: non-absorbable, co-polymer with high affinity for gliadins Immunosuppressants CCX282-B: Anti-CCR9 Blockade Hu-MiK-Beta-1: Humanized IL-15 specific antibody Immunotherapies Nexvax2: Vaccine COUR-NP-GLI: nanoparticle therapy
Intestinal Permeiabilty Theory of Mucosal Immune Homeostasis Chronic Inflammation-Allergy Normal/physiologically controlled permeability Minor barrier defect dietary/microbial Ag influx Increased permeability Massive dietary and microbial antigen influx Defensins Mucus Synthesis & Quality SIgA Mucosal Tolerance Homeostasis Anergy Regulatory DC s Macrophages Tregs IL-10/TGF-b Adapted from P. Brandtzaeg, Beneficial Microbes 2010 Inflammation - Allergy Innate or immunoregulatory defect Vicious cycle Proinflammatory Allergic cytokines Break of Tolerance Apoptosis resistant T cells Tissue damage Chronic inflammation Allergy
Total GSRS Score Change from Day 0 to Day 14 % Subjects with Gluten Toxicity Phase 2a Larazotide Acetate: Prevention of Signs & Symptoms of Gluten Exposure During Two Week Gluten Challenge 1.4 1.2 Symptoms Score (GSRS) 60 Gluten-Related Adverse Events 1 0.8 40 0.6 p = 0.001 p = 0.008 0.4 p = 0.032 p = 0.013 20 0.2 0 Disease Control Negative Control Active Treatment 0 Disease Control Negative Control Active Treatment No differences in primary endpoint of LA:MA Prevention of immunologic changes in PBMc (B cells) Daily diary: Reduction in frequency of bowel movements, abdominal discomfort & pain Safety comparable to placebo Daniel A Leffler, C P Kelly, H Z Abdallah, et al., A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease during Gluten Challenge, The American Journal of Gastroenterology doi:10.1038/ajg.2012.211
Larazotide Phase 2c: 12 week trial in patients with persistent symptoms Leffler DA et al. Gastro 2015
ALV-003 (Alvine) ALV003 DEGRADES GLUTEN UP TO 96% IN HUMAN STOMACH % Epitope Remaining by ELISA 100% DESIGN Gluten: 1,000 mg Average 92% Dosage: 300 mg ALV003 of Disease Relevant Epitopes Eliminated Gluten Bread Crumbs in Complex Meal Stomach Content Analysis: 30 min 8.7% ± 0.2% 11% ± 0.2% 8.8% ± 0.1% 4.1% ± 0.1% Control Placebo NO ALV003 Subject #1 Subject #2 Subject #3 Treatment with ALV003 Subject #4
Phase 2a ALV-003: Prevention of Gluten Induced Mucosal Injury Exposure During 6 Week Gluten Challenge Lahdeaho ML, Kaukinen K, et al., Gastro 2014
Phase 2b ALV-003: 12 week trial in patients with persistent symptoms Vh:Cd Improvement Symptom Improvement 0.3 0.25 0.2 0.15 0.1 0.05 3 2.5 2 1.5 1 0.5 0 0 Placebo 100mg 300mg 450mg 600mg 900mg Murray JA, et al., Gastro 2016
KumaMax Developed Using Computational Protein Design 1. Select Template Protease 2. Computational Design to Increase Activity 3. Test Designed Enzymes Kumamolisin from Alicyclobacillus sendaiensis Theoretical Mutation Intended to Increase Enzyme Activity Against Gliadin Substrate 4. Combine Promising Mutations Courtesy of Ingrid Swanson Pultz KumaMax Lead
KumaMax Efficiently Reduces Gluten In Foods and in Gastric Conditions EPB2/SCPEP KumaMax 10,000 ppm 84.8% 20 ppm >99.97% Courtesy of Ingrid Swanson Pultz
BL-7010 Non-absorbable, co-polymer with high affinity for gliadins
Nexvax (Nexpep) Peptide library: 18,117 12mers Dominant peptides 2,922 20mers 3 16AA Proteins Treatment shifts T cells from pro-inflammatory to tolerant response to gluten Induces tolerance in a celiac mouse model Phase 2a trials underway Nexvax administration symptoms mimicking oral gluten exposure
Courtesy of Tobias Frietag Nanoparticles
Courtesy of Tobias Frietag Nanoparticles
Development Requires Many Participants Phase Design n Duration Primary Outcome Preclinical T-cell activation, ex n/a n/a Prevention vivo duodenal biopsy or reversal of culture and/or celiac disease animal models activity Phase I Healthy control exposure, limited disease testing 10-40 1-1000 days Phase IIa Gluten challenge 30-60 4-12 weeks Phase IIb Adjunctive treatment 200-400 Phase III Adjunctive treatment? 800-2000 Safety/tolera bility Histology 12 weeks Symptoms (+/- histology) 12-26 weeks Symptoms by validated PRO (+/- histology) Phase IV Open Label 500 1 year Quality of life (+/- serology, histology) Secondary Outcomes Mechanism of action Early proof of concept Symptoms, serology Histology, serology Histology, serology Symptoms, serology, histology
Conclusions There is room for improvement in the way we manage celiac disease Novel therapeutics will significantly alter all aspects of celiac disease care, increasing diagnosis, encouraging monitoring and improving outcomes
the future of celiac disease. Leffler