Larazotide Acetate. Alessio Fasano, M.D. Mucosal Biology Research Center and Center for Celiac Research University of Maryland School of Medicine

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1 Larazotide Acetate Alessio Fasano, M.D. Mucosal Biology Research Center and Center for Celiac Research University of Maryland School of Medicine

2 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

3 Current ClinicalTrials in CD (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 AT 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 AT Trial Proteases 1 Trial

4 Cumulative Number of Celiac Disease Clinical Trials

5 Zonulin Inhibitor

6 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 Cd 5-5 Vh Cd Vh * Vh Placebo/GFD 10 mg Gluten 50 mg Gluten -25 *Significantly different from placebo Catassiet al, Am JClinNutr 2007

7 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: 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):

8 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

9 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

10 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

11 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

12 Alba Clinical Trial Summary in Celiac Disease with Larazotide Acetate Tight Junction Regulator Phase Ib - Single Dose (CLIN ) 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 (CLIN ) 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 % Bioavailability No Adverse Safety Trends Phase IIb - Multiple Dose (CLIN ) 184 celiac disease subjects Double blind, placebo controlled 6 weeks TID dosing and gluten challenge Dose ranging - 4 arms Multi-center Outpatient Study

13 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

14 La/Ma (day x) / La/Ma (day 1) % (Placebo n=7; AT-1001 n=14) Celiac Disease PoC Data Phase 1b CLIN Larazotide Acetate Blocks Acute Gluten-induced Permeability & Immune Activation Phase Ib Gastrointestinal Signs & Symptoms Intestinal Permeability 120% * GI Symptoms 2.00 Blind Gluten Challenge, 2.5gm 100% 80% * (*p=0.04) 60% 40% Placebo AT % (**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

15 Total GSRS Score Change from Day 0 to Day 14 CLIN Larazotide Acetate Prevented Signs & Symptoms of Gluten Exposure as Measured by Gastrointestinal Symptom Rating Scale Symptoms Score (GSRS) p = p = Disease Control Negative Control Active Treatment % 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)

16 Change in CeD-GSRS Score (mean, SE) CLIN Change in CeD-GSRS Reduced Symptoms of Celiac Disease Run-in Double-blind treatment period Follow-up Study visits ** Figure is Full analysis set Figure is Full analysis set p values: full data set p values: full data set

17 CLIN CeD-GSRS: Diarrhea/Abdominal Pain/Indigestion Absolute Value Change from Baseline 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

18 Relative Change in anti-ttg IgA (mean, SE) CLIN Change in Anti-transglutaminase IgA Study visits Full analysis set, n = 167 Relative change = Difference/baseline

19 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 CLIN Adverse Events 140 Treatment-Emergent (Absolute #) 60 Gluten-Related (Absolute #) 30 General Disorders (~Fatigue) 16 Skin Disorders (~Dermatitis) Safety analysis set, n= 171

20 % 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% CLIN Study (Baseline to Day 3, 12 mg QD) 1.2 CLIN Study (Baseline to Day 14, pooled active) 0.6 CLIN Study (Baseline to LDBTP, 1 mg TID) 70% % 50% % % % 10% % LDBTP, Last Double-Blind Treatment Period Visit Placebo Active

21 CLIN 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

22 AT : 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= Marsh score equivalences for analysis: Marsh 0=0 points, Marsh I=1, II=2, IIIa=3, IIIb=4, IIIc=5, IV=6 points

23 Ongoing Alba Clinical Study One Phase IIb Clinical Study is underway for Celiac Disease sponsored by Alba Therapeutics Alba CLIN 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

24 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 Phase 1, Multiple Escalating Dose in Healthy 24 Volunteers -004 Phase 2a, Multiple Dose in Controlled Celiac Patients Gluten Challenge 2 weeks Phase 2b, Dose ranging in Controlled Celiac Patients Gluten Challenge 6 weeks B Phase 2b, Controlled Celiac Patients 42 Gluten Challenge 6 weeks -011 Phase 2b, Dose ranging in Active Celiac patients, weeks Total 486 Safety Efficacy

25 Efficacy: Larazotide Acetate Reduces the Signs and Symptoms of Gluten Challenge % Subjects with Gluten Toxicity Phase IIa Aggregated Groups, Intent-to-treat Population n= P-value: Fisher s Exact Test p=0.001 p= 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

26 Relative Change in anti-ttg IgA (mean, SE) Efficacy CLIN-006: Change in anti-transglutaminase IgA Study visits Full analysis set, n = 167 Relative change = Difference/baseline

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