Larazotide Acetate Alessio Fasano, M.D. Mucosal Biology Research Center and Center for Celiac Research University of Maryland School of Medicine
Alternative/Integrative Approaches To The Gluten Free Diet Prevention Alternative Treatments Primary Prevention (Timing of gluten introduction) Secondary Prevention (Microbiome Modification) Development of genetically modified grains Inhibitors of tissue transglutaminase Cytokines and/or cytokine receptors inhibitors Detoxification of immunogenic gliadin peptides via oral peptidase supplementation Oral or intra-nasal celiac vaccines to induce tolerance Inhibitors of the effects of zonulin on intestinal permeability
Current ClinicalTrials in CD www.clinicaltrials.gov (Updated March 25 th, 2012) Registered Clinical Trials: 48 Diagnosis: 8 Dietary intervention: 8 Treatment alternative To GFD: 23 Others (co-morbidities, behavior, etc): 9 Treatment: 20 (# technologies: 6) Prevention: 3 ChemoCentryx CCR9 antagonist 1 Trial Completed: 18 Alba Therapeutics AT1001 7 Trials Alvine Pharmaceuticals ALV003 5 Trials Nexpep Pty Nexvax2 1Trial Proteases 3 Trials Princess Alexandra Hospital, Brisbane, Australia Inoculation Hookworm N. Americanus 1 Trial Active: 2 Alba Therapeutics AT1001 1 Trial Proteases 1 Trial
Cumulative Number of Celiac Disease Clinical Trials
Zonulin Inhibitor
GFD: A Very Small Amount of Gluten a Day (50 mg, a crumb of bread) Can Induce Villi Damage Change from baseline 25 Villous height and crypt depth 25 15 15 Cd 5-5 Vh Cd Vh * 5-5 -15 Vh -15-25 Placebo/GFD 10 mg Gluten 50 mg Gluten -25 *Significantly different from placebo Catassiet al, Am JClinNutr 2007
Celiac Disease is a Unique Autoimmune Disorder Environmental trigger is the ingestion of gluten Immune response to gluten triggers an inflammatory reaction in the small intestine¹ Significant morbidity associated with untreated disease Increased mortality risk due to cancer (T-cell Lymphoma, small intestinal adenocarcinoma)² Osteoporosis, Neurological syndromes, Anemia Jejunum Tight Junction Structure No approved drug for the treatment of Celiac disease Normal TJ in Control Jejunum Disrupted TJ in Celiac Disease Schulzke et al. (1999) Pediatr. Res. 43: 435-441 ¹ Rubio-Tapia, Murray, JA, et al, Increased Prevalence and Mortality in Undiagnosed Celiac Disease, Gastroenterology 2009;137:88-93 ² Mäki M et al, Eur J Epidemiol. 2006; 21 (5): 359-65
Leveraging Tight Junctions for Disease Modification Apical surface Intestinal epithelial cells Paracellular Transport Tight junctions are inter-cellular gates that open and close in response to internal and external stimuli Allows for immune surveillance Modulates immune function Regulates exchange of small molecules, proteins and cells across these barriers Tight Junction Paradigm shift in the treatment of immune mediated and inflammatory diseases (e.g. Celiac Disease, IBD, IBS, etc.) Basal surface
Gluten May Gain Access to the Gut Wall Via Increased Intestinal Permeability ( Leaky Gut ) HEALTHY NUTRIENTS GLUTEN LEAKY GUT NUTRIENTS GLUTEN CELIAC DISEASE Block tight junctions Alba is testing an experimental medicine that potentially blocks Tight Junctions
Larazotide Acetate Inhibits Gluten-Induced Permeability and Inflammation In vivo 1. Gopalakrishnan et al, Larazotide acetate regulates epithelial tight junctions in vitro and in vivo, Peptides, February 27, 2012 Gluten sensitized HLA-HCD4/DQ8 transgenic mice were fed with gluten in the presence or absence Pandey of N larazotide et al. Peptide acetate (in and press) intestinal changes were determined by TEM
Larazotide Acetate Inhibits Gluten-Induced Actin Rearrangement Resulting in Stabilization of TJ Proteins ZO-1 IEC6 cells were treated with PT gliadin +/- Larazotide Acetate for 1 hour 1. Gopalakrishnan et al, Larazotide acetate regulates epithelial tight junctions in vitro and in vivo, Peptides, February 27, 2012
Alba Clinical Trial Summary in Celiac Disease with Larazotide Acetate Tight Junction Regulator Phase Ib - Single Dose (CLIN1001-002) 21 Celiac disease subjects Double blind, placebo controlled 3 days QD, single gluten challenge on day 2 In-patient study Completed March 2006 Phase IIa - Multiple Dose (CLIN1001-004) 86 celiac disease subjects Double blind, placebo controlled 2 weeks TID dosing and gluten challenge Dose ranging - 7 arms Multi-center Outpatient Study Completed March 2007 0% Bioavailability No Adverse Safety Trends Phase IIb - Multiple Dose (CLIN1001-006) 184 celiac disease subjects Double blind, placebo controlled 6 weeks TID dosing and gluten challenge Dose ranging - 4 arms Multi-center Outpatient Study
Safety Profile of Larazotide Acetate to Date Larazotide acetate acts locally in the gastrointestinal tract No systemic exposure, no measurable plasma drug levels in any clinical study No immunogenicity, no antibody development in any clinical study No toxicity observed to date in 24 completed animal toxicology studies No safety signals in ~300 celiac subjects exposed to larazotide acetate up to 8 weeks To date, safety comparable to placebo
La/Ma (day x) / La/Ma (day 1) % (Placebo n=7; AT-1001 n=14) Celiac Disease PoC Data Phase 1b CLIN1001-002 Larazotide Acetate Blocks Acute Gluten-induced Permeability & Immune Activation Phase Ib Gastrointestinal Signs & Symptoms Intestinal Permeability 120% * 0.018 GI Symptoms 2.00 Blind Gluten Challenge, 2.5gm 100% 80% *0.017 1.75 (*p=0.04) 60% 40% Placebo AT-1001 20% 1.50 1.25 (**p=0.07) Placebo n = 7 0% GI Symptoms Abdominal Pain Constipation Diarrhea Flatulence Nausea Vomiting 1.00 Larazotide Acetate n = 14 Serum IFN-g Dimension 0.75 Day 1 Day 2 Day 3 Day 7
Total GSRS Score Change from Day 0 to Day 14 CLIN1001-004 Larazotide Acetate Prevented Signs & Symptoms of Gluten Exposure as Measured by Gastrointestinal Symptom Rating Scale 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Symptoms Score (GSRS) p = 0.032 p = 0.013 Disease Control Negative Control Active Treatment 40 20 % Subjects with Gluten Toxicity 60 0 Gluten-Related Adverse Events p=0.001 * Disease Control Negative Control (Gluten + placebo) (No Gluten + placebo or larazotide acetate) p=0.008 * Active Treatment (Gluten + Larazotide acetate)
Change in CeD-GSRS Score (mean, SE) CLIN1001-006 Change in CeD-GSRS Reduced Symptoms of Celiac Disease Run-in Double-blind treatment period Follow-up 0.19 0.03 0.003 Study visits ** Figure is Full analysis set Figure is Full analysis set p values: full data set p values: full data set
CLIN1001-006 CeD-GSRS: Diarrhea/Abdominal Pain/Indigestion Absolute Value Change from Baseline 0.19 0.34 0.24 0.03 0.01 0.003 Mean ODBTP (p): 1mg -0.1 (p=0.0009); 4mg 0.19 (p=0.18); 8 mg 0.1 (p=0.1) Figure is Full analysis set p values: full data set
Relative Change in anti-ttg IgA (mean, SE) CLIN1001-006 Change in Anti-transglutaminase IgA 0.03 0.01 0.008 0.02 0.009 0.005 Study visits Full analysis set, n = 167 Relative change = Difference/baseline
Total Number of Adverse Events Number of Gluten-Related Adverse Events Percent of Patients with General Disorders as Adverse Events Percent of Patients with Skin Disorders as Adverse Events CLIN1001-006 Adverse Events 140 Treatment-Emergent (Absolute #) 60 Gluten-Related (Absolute #) 30 General Disorders (~Fatigue) 16 Skin Disorders (~Dermatitis) 120 50 25 14 100 40 20 12 10 80 30 15 8 60 40 20 10 6 4 20 10 5 2 0 0 0 0 Safety analysis set, n= 171
% of patients with symptoms Change in GSRS domains Change in GSRS domains Larazotide Acetate Consistently Reduced Gastro- Intestinal Symptoms in 3 Gluten-Challenge Clinical Trials 80% CLIN1001-002 Study (Baseline to Day 3, 12 mg QD) 1.2 CLIN1001-004 Study (Baseline to Day 14, pooled active) 0.6 CLIN1001-006 Study (Baseline to LDBTP, 1 mg TID) 70% 1 0.5 60% 50% 0.8 0.4 40% 0.6 0.3 30% 0.4 0.2 20% 10% 0.2 0.1 0% 0 0-0.1-0.2 LDBTP, Last Double-Blind Treatment Period Visit Placebo Active
CLIN1001-006 Conclusions LA:MA (Primary Endpoint) proved ineffective as dose finding assay in a 6 week out-patient study Confirmed positive results in GSRS (pre-specified secondary endpoint) measuring signs and symptoms of gluten exposure Prevention of the generation of anti-ttg antibodies after 6 week gluten exposure (pre-specified secondary endpoint) Excellent Safety and Tolerability Profile Reduction in gluten-related adverse events
AT1001-011: Active Celiac Disease Phase II Study Marsh by Compliance with the GFD between D28 and LDBTP GFD COMPLIANCE D28-LDBTP GFD NON-COMPLIANCE D28-LDBTP N=4 0.9 0.82 0.35 0.04 Marsh score equivalences for analysis: Marsh 0=0 points, Marsh I=1, II=2, IIIa=3, IIIb=4, IIIc=5, IV=6 points
Ongoing Alba Clinical Study One Phase IIb Clinical Study is underway for Celiac Disease sponsored by Alba Therapeutics Alba CLIN1001-012 Celiac Disease Biopsy proven celiac disease at least 12 months ago Attempting a Gluten Free Diet for at least 12 months Positive/Measurable Serology (Anti-tTG or DGP) Other entry criteria
Comprehensive Phase 1-2 Program of Larazotide Acetate in Celiac Disease has Studied ~500 Patients TRIAL DESIGN N -001 Phase 1, Single Escalating Dose in Healthy 24 Volunteers -002 Phase 1b, Multiple Dose in Controlled Celiac Patients 21-003 Phase 1, Multiple Escalating Dose in Healthy 24 Volunteers -004 Phase 2a, Multiple Dose in Controlled Celiac Patients Gluten Challenge 2 weeks 86-006 Phase 2b, Dose ranging in Controlled Celiac Patients Gluten Challenge 6 weeks 184-06B Phase 2b, Controlled Celiac Patients 42 Gluten Challenge 6 weeks -011 Phase 2b, Dose ranging in Active Celiac patients, 8 105 weeks Total 486 Safety Efficacy
Efficacy: Larazotide Acetate Reduces the Signs and Symptoms of Gluten Challenge % Subjects with Gluten Toxicity Phase IIa Aggregated Groups, Intent-to-treat Population n=86 80 60 P-value: Fisher s Exact Test 40 20 p=0.001 p=0.008 0 Gluten Challenge Gluten Placebo Active Treatment (P/P & 8mg/P) (0.25/1/4/8mg + Gluten) Symptoms of Gluten Toxicity: Dermatitis Herpetiformis, diarrhea, elevated LFTs, nausea gas, abdominal pain, aphthous ulcers and dyspepsia Leffler D. et al DDW 2008
Relative Change in anti-ttg IgA (mean, SE) Efficacy CLIN-006: Change in anti-transglutaminase IgA 0.03 0.01 0.008 0.02 0.009 0.005 Study visits Full analysis set, n = 167 Relative change = Difference/baseline