Supplemental Table 1: Moderate and severe definitions of Celiac Disease Symptom Diary symptoms CDSD Symptom Diarrhea Constipation Abdominal Pain Bloating Nausea Tiredness Moderate Once or twice between Days 15 21 or Days 22 28 Severe Three or more times on a single day between Days 15 21 or Days 22 28 One or 2 spontaneous bowel movements between Days 15 21 or Days 22 28 Scale score of 4, 5, or 6 Scale score of 7, 8, 9, or 10 between Days 15 28 between Days 15 28 Moderate between Days 15 Severe or Very Severe 28 between Days 15 28 Moderate between Days 15 Severe or Very Severe 28 between Days 15 28 Moderate between Days 15 Severe or Very Severe 28 with the presence of, between Days 15 28 with the regardless of severity, presence of, regardless of diarrhea, abdominal pain, severity, diarrhea, abdominal bloating, or nausea on the pain, bloating, or nausea on the same day same day CDSD = Celiac Disease Symptom Diary 1
Supplemental Table 2: Inclusion and exclusion criteria Inclusion Criteria 1. Age 18 to 80 years 2. Physician-diagnosed celiac disease patients with documented history of biopsyproven celiac disease; patients previously diagnosed only by positive serology and clinical response to exclusion of dietary gluten require biopsy confirmation of celiac disease prior to randomization 3. Self-reported to be on a gluten-free diet for at least 11 months prior to enrollment 4. Experienced at least one self-reported moderate or severe symptom included in the Celiac Disease Symptom Diary, probably/likely as a result of gluten exposure, during the 28-day period prior to screening 5. Had daily telephone access in order to complete the Celiac Disease Symptom Diary 6. Agree to maintain dosing of approved prescribed and over-the-counter medications throughout the course of the study 7. Willing to take study treatment 3 times each day with each major meal, with minimal ingestion outside of these meals 8. Willing to undergo 2 on-study upper gastrointestinal endoscopies with duodenal biopsies 9. Willing and able to comply with all study procedures 10. Signed informed consent 2
a. US and Canada: Must be able to read and understand English; Europe: Must have been able to read and understand the native language of the patient s country Exclusion Criteria 1. History of known Immunoglobulin E -mediated reaction to wheat (i.e., wheat allergy ) 2. Currently untreated or active peptic ulcer disease, esophagitis (Los Angeles Classification Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic colitis 3. Active dermatitis herptiformis 4. Patients with known rapid gastric emptying (e.g., post-bariatric surgery, Billroth I or II surgery) 5. Chronic infectious gastrointestinal illness, or acute infectious gastrointestinal illness within the 4 week period prior to enrollment 6. Known Refractory Celiac Disease (RCD1 or RCD2). Refractory celiac disease is characterized by persistent symptoms, severe malabsorption, and intestinal damage despite strict adherence to a gluten-free diet (in patients with RCD1, the intraepithelial lymphocyte phenotype is normal; in RCD2, there is a clonal aberrant phenotype of the intraepithelial lymphocyte) 7. Screening laboratory values a. Elevated liver function tests (alanine aminotransferase, aspartate transaminase, alkaline phosphatase or gamma-glutamyl transferase > 2.5x upper limit of normal 3
b. Total bilirubin > 2x upper limits of normal c. Serum creatinine > 1.5x upper limits of normal d. Calcium < 8.0 mg/dl e. Serum potassium < 3.0 meq/l, > 5.5 meq/l f. Hemoglobin < 8.5 g/dl g. Platelet count < 75.0 x 10 9 /L or 75,000/mm 3 h. Total white blood cell count < 2.5 x 10 9 /L or 2500/mm 3 i. Total lymphocyte < 0.8 x 10 9 /L or 800/mm 3 8. For women of childbearing potential, positive pregnancy test at screening, or were planning to become pregnant during the course of the study, or unwilling to practice effective birth control during the study 9. Expected use of anticoagulants or antiplatelet agents (e.g., warfarin, heparin, or clopidogrel or similar class), other than mini-dose aspirin (e.g., 81 mg) during the week prior to intestinal biopsies that, in the opinion of the endoscopist, would affect the safety of obtaining the biopsies 10. Change of dose or frequency of systemic glucocorticosteroid medications, oral budesonide, or mesalamine within 28-days prior to enrollment at Visit 2 and/or expected to change during the study 11. Use of angiotensin II receptor blockers within 28 days prior to enrollment at Visit 2 and during the study 4
12. History of alcohol abuse or habitual use of illicit drugs (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, and opiates, including abuse of prescription opiates) within the past 6 months 13. Received any experimental drug within 30 days of enrollment at Visit 2; in the case of experimental protein therapeutics or vaccines, at least 6 months prior to enrollment 14. Other than oral contraceptives, use of prescribed medications or over-the-counter medications that in the opinion of the investigator might interfere with the study 15. Any medical condition, which, in the opinion of the study investigator, could have adversely affected the patient s participation in the trial, including the ability to tolerate 2 upper gastrointestinal endoscopies with duodenal biopsies, or affect the trial integrity 16. Known allergy or hypersensitivity to any of the components of ALV003 (including sulfites), E. coli, or E. coli-derived proteins to 24 Treatment Exclusion Criteria 1. Failed to complete Study Period 2, including the 12-week endoscopy and biopsy 2. Insufficient compliance with study medication of at least 80% during Study Period 2 3. Insufficient compliance with Celiac Disease Symptom Diary completion of at least 75% during Study Period 2 4. Unwilling to undergo an additional endoscopy with duodenal biopsy at Week 24 5. Failed to maintain gluten-free diet 5
6. For women of childbearing potential, positive pregnancy test at Visit 6 7. Clinically significant findings that could affect continued patient safety and/or integrity of the study 8. Did not sign an addendum to informed consent 6
Supplemental Table 3: Demographics and baseline characteristics Modified Intent-to- Treat treatment extension population Treatment Group (n = 106) Placebo (n = 30) 100 mg (n = 14) 300 mg (n = 22) 450 mg (n = 12) 600 mg (n = 16) 900 mg (n = 12) Sex (n, %) Male 4 (13.3%) 4 (28.6%) 9 (40.9%) 3 (25.0%) 5 (31.3%) 0 Female 26 (86.7%) 10 (71.4%) 13 (59.1%) 9 (75.0%) 11 (68.8%) 12 (100%) Age (Years) Mean (SD) 49.3 (13.45) 48.8 (17.39) 57.2 (12.41) 47.3 (13.50) 48.9 (12.47) 52.1 (13.70) Median 52.0 51.2 59.6 45.9 50.0 58.7 Min, Max 23.3, 71.0 20.4, 75.2 25.5, 74.6 28.4, 72.3 22.8, 72.0 29.1, 67.7 Ethnicity (n, %) Hispanic 1 (3.3%) 1 (7.1%) 0 0 1 (6.3%) 0 Non-hispanic 29 (96.7%) 13 (92.9%) 22 (100%) 12 (100%) 15 (93.8%) 12 (100%) Race (n, %) White 29 (96.7%) 13 (92.9%) 22 (100%) 11 (91.7%) 16 (100%) 12 (100%) Black or African American 1 (3.3%) 0 0 0 0 0 American Indian or Alaskan Native Asian 0 0 0 0 0 0 0 1 (7.1%) 0 1 (8.3%) 0 0 Other 0 0 0 0 0 0 Height (cm) Mean (SD) 166.6 (8.09) 167.0 (7.40) 169.3 (8.04) 165.6 (8.34) 166.1 (8.33) 158.4 (4.75) Median 167.3 167.6 171.2 163.1 168.8 157.8 Min, Max 144.8, 182.9 152.4, 184.0 151.1, 182.9 155.6, 182.9 153.6, 182.9 152.4, 165.1 Body Mass Index (kg/m 2 ) Mean (SD) 28.1 (5.44) 27.8 (6.30) 27.3 (3.37) 29.4 (7.08) 29.3 (7.50) 25.7 (3.89) Median 27.3 28.6 27.4 26.4 27.0 26.5 Min, Max 18.9, 40.9 17.0, 44.5 20.7, 32.7 23.2, 47.9 21.4, 47.8 19.1, 30.2 Vh:Cd Eligibility Mean (SD) 1.27 (0.591) 1.40 (0.459) 1.20 (0.552) 1.46 (0.560) 1.16 (0.647) 1.31 (0.474) Median 1.30 1.30 1.35 1.60 1.35 1.35 Min, Max 0.00, 2.00 0.40, 2.00 0.00, 1.90 0.20, 2.00 0.00, 2.00 0.20, 1.80 Vh:Cd = villous height to crypt depth 7
Supplemental Table 4: Summary of villous height to crypt depth in the treatment extension (week 24) Modified Intent-to-Treat population Vh:Cd Baseline Treatment Group (N=106) Placebo (N=30) 100 mg (N=14) 300 mg (N=22) 450 mg (N=12) 600 mg (N=16) Number of Patients 30 14 22 12 16 12 900 mg (N=12) Mean (SD) 1.44 (0.599) 1.48 (0.527) 1.38 (0.600) 1.70 (0.434) 1.31 (0.724) 1.50 (0.561) Median 1.61 1.33 1.49 1.82 1.48 1.51 Min, Max 0.00, 2.14 0.61, 2.43 0.00, 2.37 0.69, 2.12 0.00, 2.67 0.25, 2.33 Number of Patients 30 14 22 12 16 12 Mean (SD) 1.72 (0.660) 1.69 (0.470) 1.67 (0.741) 1.74 (0.631) 1.41 (0.715) 1.85 (0.742) Median 1.90 1.74 1.76 1.79 1.48 1.81 Min, Max 0.06, 2.99 0.51, 2.22 0.00, 2.96 0.91, 2.70 0.14, 2.56 0.92, 2.81 Change from Baseline at Number of Patients 30 14 22 12 16 12 Mean (SD) 0.28 (0.353) 0.21 (0.403) 0.29 (0.297) 0.05 (0.629) 0.10 (0.396) 0.35 (0.488) Median 0.29 0.22 0.26 0.23 0.06 0.26 Min, Max -0.36, 1.15-0.34, 1.08-0.16, 0.98-1.18, 0.77-0.61, 0.87-0.25, 1.48 p-value 0.0002 0.0736 0.0002 0.8076 0.3397 0.0305 Week 24 Number of Patients 30 14 22 12 16 12 Mean (SD) 1.85 (0.633) 1.85 (0.487) 1.69 (0.657) 1.89 (0.622) 1.53 (0.877) 1.99 (0.886) Median 1.94 1.92 1.83 1.94 1.70 1.93 Min, Max 0.10, 2.74 0.41, 2.43 0.00, 2.78 0.19, 2.57 0.30, 2.96 0.03, 3.26 Change from Baseline at Week 24 Number of Patients 30 14 22 12 16 12 Mean (SD) 0.41 (0.456) 0.38 (0.527) 0.31 (0.316) 0.19 (0.445) 0.22 (0.481) 0.49 (0.831) Median 0.33 0.38 0.37 0.17 0.31 0.52 Min, Max -0.33, 1.82-0.34, 1.27-0.52, 0.80-0.60, 0.92-1.08, 0.92-1.47, 1.92 p-value <.0001 0.0189 0.0002 0.1601 0.0931 0.0646 Vh:Cd = villous height to crypt depth 8
Supplemental Table 5: Analysis of covariance of the change from baseline of villous height to crypt depth in the treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 Vh:Cd N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 30 1.44 30 0.28 0.15, 0.41 100 mg 14 1.48 14 0.21-0.02, 0.44 300 mg 22 1.38 22 0.29 0.15, 0.42 450 mg 12 1.70 12 0.05-0.35, 0.45 600 mg 16 1.31 16 0.10-0.11, 0.31 900 mg 12 1.50 12 0.35 0.04, 0.66 Treatment Effect 2 600mg + 900mg vs Placebo -0.06-0.276, 0.155 0.5776 600mg vs Placebo -0.19-0.445, 0.061 0.1345 600mg + 450mg vs Placebo -0.20-0.412, 0.019 0.0735 300mg + 450mg vs Placebo -0.10-0.309, 0.110 0.3478 300mg vs Placebo 0.00-0.227, 0.231 0.9863 300mg + 100mg vs Placebo -0.03-0.236, 0.172 0.7560 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status Vh:Cd = villous height to crypt depth; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 9
Supplemental Table 6: Summary of cluster of differentiation 3 positive intraepithelial lymphocytes in the (week 12) Modified Intent-to-Treat population CD3+ IEL (Cells/100 epithelial cells) Baseline Treatment Group (N=405) Placebo (N=125) 100 mg (N=47) 300 mg (N=77) 450 mg (N=39) 600 mg (N=80) 900 mg (N=37) Number of Patients 125 47 77 39 80 37 Mean (SD) 51.3 (20.66) 50.1 (18.52) 57.2 (23.68) 50.9 (23.81) 51.8 (24.08) 52.9 (22.59) Median 52.0 52.5 55.5 47.0 54.8 52.5 Min, Max 8.5, 105.5 14.5, 100.5 14.5, 112.5 13.0, 108.5 8.0, 106.5 9.5, 103.0 Number of Patients 125 47 77 39 80 37 Mean (SD) 55.5 (22.67) 55.9 (20.75) 65.9 (24.81) 57.8 (20.76) 59.4 (27.06) 59.0 (23.02) Median 55.0 55.5 60.0 56.5 54.8 59.5 Min, Max 7.5, 115.5 14.5, 107.0 21.0, 132.0 24.0, 116.0 6.5, 126.0 18.0, 120.0 Change from Baseline at Number of Patients 125 47 77 39 80 37 Mean (SD) 4.2 (18.44) 5.8 (18.82) 8.7 (17.96) 6.9 (20.95) 7.6 (21.15) 6.0 (16.15) Median 3.0 7.5 8.0 8.0 7.5 5.0 Min, Max -40.0, 52.5-39.0, 50.5-32.0, 58.0-64.5, 46.5-62.5, 53.0-30.0, 43.0 p-value 0.0116 0.0412 <.0001 0.0459 0.0018 0.0293 CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocytes 10
Supplemental Table 7: Analysis of covariance of the change from baseline of cluster of differentiation 3 positive intraepithelial lymphocytes in the (week 12) Modified Intent-to- Treat population Baseline Change from Baseline Treatment Difference 1 CD3+ IEL (Cells/100 epithelial cells) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 125 51.3 125 4.2 1.0, 7.5 100 mg 47 50.1 47 5.8 0.2, 11.3 300 mg 77 57.2 77 8.7 4.7, 12.8 450 mg 39 50.9 39 6.9 0.1, 13.7 600 mg 80 51.8 80 7.6 2.9, 12.3 900 mg 37 52.9 37 6.0 0.6, 11.4 Treatment Effect 2 600mg + 900mg vs Placebo 3.1-1.52, 7.78 0.1867 600mg vs Placebo 3.6-1.39, 8.56 0.1577 600mg + 450mg vs Placebo 3.2-1.45, 7.76 0.1786 300mg + 450mg vs Placebo 4.5-0.11, 9.14 0.0556 300mg vs Placebo 6.3 1.25, 11.36 0.0147 300mg + 100mg vs Placebo 3.8-0.70, 8.25 0.0982 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocytes; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 11
Supplemental Table 8: Summary of cluster of differentiation 3 positive intraepithelial lymphocyte treatment extension (week 24) Modified Intent-to-Treat population CD3+ IEL (Cells/100 epithelial cells) Baseline Treatment Group (N=106) Placebo (N=30) 100 mg (N=14) 300 mg (N=22) 450 mg (N=12) 600 mg (N=16) Number of Patients 30 14 22 12 16 12 900 mg (N=12) Mean (SD) 55.3 (21.58) 44.6 (16.62) 53.7 (24.04) 51.3 (28.14) 55.3 (26.34) 54.0 (26.25) Median 59.3 42.8 55.5 51.8 57.3 51.5 Min, Max 15.5, 98.5 21.5, 79.0 14.5, 105.5 22.5, 108.5 8.0, 103.0 9.5, 103.0 Number of Patients 30 14 22 12 16 12 Mean (SD) 54.5 (23.42) 54.9 (21.97) 62.3 (25.73) 55.0 (13.14) 54.3 (26.89) 58.8 (21.61) Median 53.0 52.0 57.5 55.0 46.0 58.0 Min, Max 14.5, 115.5 25.5, 107.0 22.0, 112.5 34.0, 74.5 10.5, 96.5 18.0, 104.0 Change from Baseline at Number of Patients 30 14 22 12 16 12 Mean (SD) -0.8 (16.95) 10.3 (19.68) 8.6 (17.03) 3.8 (24.43) -1.0 (22.70) 4.8 (10.35) Median -0.3 9.8 9.3 6.5 0.3 6.3 Min, Max -32.0, 52.5-17.5, 50.5-12.5, 49.0-64.5, 31.0-62.5, 37.0-23.0, 17.5 p-value 0.7896 0.0723 0.0280 0.6055 0.8625 0.1403 Week 24 Number of Patients 30 14 22 12 16 12 Mean (SD) 61.7 (25.90) 62.9 (24.68) 60.0 (28.20) 55.3 (20.26) 59.7 (24.30) 59.0 (30.45) Median 55.0 58.8 57.5 56.3 64.3 54.8 Min, Max 19.0, 120.0 28.0, 107.5 17.5, 119.5 20.0, 81.5 17.0, 101.0 22.5, 125.0 Change from Baseline at Week 24 Number of Patients 30 14 22 12 16 12 Mean (SD) 6.4 (21.65) 18.3 (19.36) 6.3 (20.14) 4.0 (20.86) 4.4 (19.05) 5.0 (24.70) Median -0.3 14.5 4.5 0.0 7.0 2.0 Min, Max -24.5, 56.0-15.0, 47.0-28.0, 50.5-32.0, 34.0-29.0, 45.0-27.0, 67.5 p-value 0.1171 0.0037 0.1574 0.5160 0.3695 0.5012 CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocyte 12
Supplemental Table 9: Analysis of covariance of the change from baseline of cluster of differentiation 3 positive intraepithelial lymphocytes in the treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 CD3+ IEL (Cells/100 epithelial cells) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 30 55.3 30-0.8-7.2, 5.5 100 mg 14 44.6 14 10.3-1.1, 21.6 300 mg 22 53.7 22 8.6 1.0, 16.1 450 mg 12 51.3 12 3.8-11.8, 19.3 600 mg 16 55.3 16-1.0-13.1, 11.1 900 mg 12 54.0 12 4.8-1.8, 11.3 Treatment Effect 2 600mg + 900mg vs Placebo 2.7-6.18, 11.66 0.5442 600mg vs Placebo -0.4-10.81, 10.08 0.9454 600mg + 450mg vs Placebo 1.4-7.56, 10.28 0.7622 300mg + 450mg vs Placebo 5.9-2.70, 14.59 0.1755 300mg vs Placebo 8.8-0.67, 18.28 0.0682 300mg + 100mg vs Placebo 8.2-0.31, 16.66 0.0588 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status CD3+ - cluster of differentiation 3 positive; IEL = intraepithelial lymphocyte; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 13
Supplemental Table 10: Summary of tissue transglutaminase-2-iga serology in the (week 12) Modified Intent-to-Treat population TG2-IgA (U/mL) Baseline Treatment Group (N=404) Placebo (N=126) 100 mg (N=48) 300 mg (N=76) 450 mg (N=39) 600 mg (N=77) 900 mg (N=38) Number of Patients 126 48 76 39 77 38 Mean (SD) 10.5 (22.82) 6.2 (12.35) 9.8 (21.07) 4.5 (8.15) 8.7 (20.09) 11.3 (24.73) Median 2.0 2.0 2.0 2.0 2.0 2.0 Min, Max 2, 100 2, 79 2, 100 2, 44 2, 100 2, 100 Number of Patients 126 48 76 39 77 38 Mean (SD) 10.7 (22.86) 6.1 (14.43) 9.6 (20.60) 5.9 (13.24) 9.2 (21.98) 10.4 (23.19) Median 2.0 2.0 2.0 2.0 2.0 2.0 Min, Max 2, 100 2, 96 2, 100 2, 75 2, 100 2, 100 Change from Baseline at Number of Patients 126 48 76 39 77 38 Mean (SD) 0.2 (8.80) -0.1 (4.50) -0.2 (4.26) 1.5 (5.34) 0.4 (6.81) -0.9 (10.46) Median 0.0 0.0 0.0 0.0 0.0 0.0 Min, Max -35, 59-13, 17-20, 21-2, 31-27, 48-44, 34 p-value 0.7929 0.8985 0.6485 0.0901 0.5939 0.5801 TG2 = tissue transglutaminase-2 14
Supplemental Table 11: Analysis of covariance of the change from baseline in tissue transglutaminase-2-iga (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 TG2-IgA (U/mL) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 126 10.5 126 0.2-1.3, 1.8 100 mg 48 6.2 48-0.1-1.4, 1.2 300 mg 76 9.8 76-0.2-1.2, 0.7 450 mg 39 4.5 39 1.5-0.2, 3.2 600 mg 77 8.7 77 0.4-1.1, 2.0 900 mg 38 11.3 38-0.9-4.4, 2.5 Treatment Effect 2 600mg + 900mg vs Placebo -0.5-2.3, 1.4 0.6310 600mg vs Placebo 0.1-1.9, 2.2 0.8960 600mg + 450mg vs Placebo 0.6-1.3, 2.5 0.5359 300mg + 450mg vs Placebo 0.3-1.6, 2.2 0.7643 300mg vs Placebo -0.5-2.5, 1.6 0.6498 300mg + 100mg vs Placebo -0.5-2.3, 1.3 0.6082 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status TG2 = tissue transglutaminase-2; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 15
Supplemental Table 12: Summary of tissue transglutaminase-2-iga serology in the treatment extension (week 24) Modified Intent-to-Treat population TG2-IgA (U/mL) Baseline Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients 30 14 23 12 16 12 900 mg (N=12) Mean (SD) 8.5 (19.09) 4.6 (8.21) 15.3 (27.80) 3.1 (3.75) 15.8 (33.06) 11.9 (23.21) Median 2.0 2.0 2.0 2.0 2.0 2.0 Min, Max 2, 100 2, 33 2, 100 2, 15 2, 100 2, 65 Number of Patients 30 14 23 12 15 12 Mean (SD) 12.1 (23.32) 3.7 (4.75) 14.2 (26.66) 4.3 (6.88) 16.6 (33.96) 5.9 (9.08) Median 2.0 2.0 2.0 2.0 2.0 2.0 Min, Max 2, 87 2, 20 2, 100 2, 26 2, 100 2, 29 Change from Baseline at Number of Patients 30 14 23 12 15 12 Mean (SD) 3.6 (13.50) -0.9 (3.56) -1.1 (5.17) 1.3 (3.19) -0.1 (2.47) -6.0 (14.60) Median 0.0 0.0 0.0 0.0 0.0 0.0 Min, Max -13, 59-13, 2-20, 9 0, 11-7, 5-44, 1 p-value [1] 0.1585 0.3471 0.3242 0.2024 0.8377 0.1824 Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) 8.5 (18.82) 3.8 (4.23) 12.0 (23.32) 5.1 (8.10) 20.8 (36.76) 7.6 (14.34) Median 2.0 2.0 2.0 2.0 3.0 2.0 Min, Max 2, 100 2, 18 2, 100 2, 30 2, 100 2, 51 Change from Baseline at Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) 0.0 (5.91) -0.9 (4.17) -3.3 (9.31) 2.0 (4.55) 4.9 (20.43) -4.3 (18.21) Median 0.0 0.0 0.0 0.0 0.0 0.0 Min, Max -17, 20-15, 3-31, 8 0, 15-8, 81-60, 15 p-value 1.0000 0.4552 0.1028 0.1563 0.3490 0.4273 TG2 = tissue transglutaminase-2 16
Supplemental Table 13: Analysis of covariance of the change from baseline in the tissue transglutaminase-2-iga treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 TG2-IgA (U/mL) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 30 8.5 30 3.6-1.5, 8.6 100 mg 14 4.6 14-0.9-3.0, 1.1 300 mg 23 15.3 23-1.1-3.3, 1.1 450 mg 12 3.1 12 1.3-0.8, 3.3 600 mg 16 15.8 15-0.1-1.5, 1.2 900 mg 12 11.9 12-6.0-15.3, 3.3 Treatment Effect 2 600mg + 900mg vs Placebo -5.7-10.5, -0.9 0.0197 600mg vs Placebo -2.7-8.4, 2.9 0.3435 600mg + 450mg vs Placebo -2.9-7.6, 1.9 0.2314 300mg + 450mg vs Placebo -3.5-8.0, 1.0 0.1296 300mg vs Placebo -4.0-8.9, 1.0 0.1161 300mg + 100mg vs Placebo -4.4-8.8, 0.0 0.0519 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status TG2 = tissue transglutaminase-2; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 17
DGP-IgA (U) Baseline Supplemental Table 14: Summary of deamidated gliadin peptide-iga serology in the (week 12) Modified Intent-to-Treat population Treatment Group (N=404) Placebo (N=126) 100 mg (N=48) 300 mg (N=76) 450 mg (N=39) 600 mg (N=77) Number of Patients 126 48 76 39 77 38 900 mg (N=38) Mean (SD) 25.8 (32.88) 24.5 (28.19) 24.4 (29.42) 20.6 (28.75) 28.3 (33.08) 23.6 (30.47) Median 9.0 11.5 11.5 8.0 11.0 10.5 Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Number of Patients 126 48 76 39 77 38 Mean (SD) 24.5 (31.50) 24.3 (27.94) 24.3 (26.15) 24.6 (31.38) 27.1 (31.14) 22.6 (26.94) Median 9.0 12.0 15.0 10.0 12.0 11.5 Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Change from Baseline at Number of Patients 126 48 76 39 77 38 Mean (SD) -1.2 (10.91) -0.2 (9.48) -0.1 (8.02) 4.0 (8.80) -1.2 (9.51) -1.0 (17.21) Median 0.0 0.0 0.0 1.0 0.0 0.0 Min, Max -60, 41-43, 17-27, 32-8, 30-42, 24-63, 66 p-value 0.2110 0.8797 0.8755 0.0069 0.2587 0.7153 DGP = deamidated gliadin peptide 18
Supplemental Table 15: Analysis of covariance of the change from baseline in deamidated gliadin peptide-iga (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgA (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 126 25.8 126-1.2-3.1, 0.7 100 mg 48 24.5 48-0.2-3.0, 2.5 300 mg 76 24.4 76-0.1-2.0, 1.7 450 mg 39 20.6 39 4.0 1.2, 6.9 600 mg 77 28.3 77-1.2-3.4, 0.9 900 mg 38 23.6 38-1.0-6.7, 4.6 Treatment Effect 2 600mg + 900mg vs Placebo 0.2-2.5, 2.8 0.8918 600mg vs Placebo 0.3-2.6, 3.2 0.8362 600mg + 450mg vs Placebo 2.5-0.1, 5.1 0.0632 300mg + 450mg vs Placebo 2.8 0.2, 5.4 0.0382 300mg vs Placebo 0.9-2.0, 3.8 0.5432 300mg + 100mg vs Placebo 0.9-1.7, 3.4 0.4944 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 19
DGP-IgA (U) Baseline Supplemental Table 16: Summary of deamidated gliadin peptide-iga serology in the treatment extension (week 24) Modified Intent-to-Treat population Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients 30 14 23 12 16 12 900 mg (N=12) Mean (SD) 25.7 (30.38) 17.2 (21.33) 31.3 (35.29) 21.8 (25.20) 33.2 (36.48) 22.1 (25.25) Median 9.0 9.5 9.0 11.5 16.0 9.0 Min, Max 3, 95 4, 87 3, 100 4, 80 3, 100 3, 69 Number of Patients 30 14 23 12 15 12 Mean (SD) 26.6 (33.33) 16.9 (24.69) 26.7 (30.80) 25.3 (30.56) 31.3 (34.85) 17.2 (13.95) Median 11.0 10.0 6.0 12.5 17.0 16.5 Min, Max 2, 100 3, 100 3, 100 3, 96 3, 100 2, 42 Change from Baseline at Number of Patients 30 14 23 12 15 12 Mean (SD) 0.9 (11.30) -0.4 (5.12) -4.6 (8.06) 3.4 (7.82) -3.8 (8.98) -4.9 (13.94) Median 0.0-0.5-1.0 1.5-1.0 0.5 Min, Max -32, 41-9, 13-27, 2-8, 16-29, 12-37, 12 p-value 0.6658 0.7983 0.0118 0.1584 0.1234 0.2473 Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) 26.0 (30.87) 20.8 (24.77) 32.1 (34.63) 25.8 (28.96) 36.6 (40.66) 23.5 (24.77) Median 14.0 12.5 12.0 15.0 17.0 12.0 Min, Max 2, 100 4, 97 3, 100 3, 100 3, 100 4, 69 Change from Baseline at Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) 0.3 (12.19) 3.6 (7.09) 0.8 (18.69) 3.9 (8.64) 3.4 (23.66) 1.4 (23.06) Median 0.0 2.5-1.0 2.5 0.0 1.0 Min, Max -23, 41-6, 23-57, 54-6, 20-29, 87-48, 58 p-value 0.8937 0.0820 0.8341 0.1446 0.5697 0.8353 DGP = deamidated gliadin peptide 20
Supplemental Table 17: Analysis of covariance of the change from baseline in the deamidated gliadin peptide-iga treatment extension (week 24) MITT population Baseline Change from Baseline Treatment Difference 1 DGP-IgA (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 30 25.7 30 0.9-3.3, 5.1 100 mg 14 17.2 14-0.4-3.3, 2.6 300 mg 23 31.3 23-4.6-8.1, -1.1 450 mg 12 21.8 12 3.4-1.6, 8.4 600 mg 16 33.2 15-3.8-8.8, 1.2 900 mg 12 22.1 12-4.9-13.8, 3.9 Treatment Effect 2 600mg + 900mg vs Placebo -4.7-9.8, 0.3 0.0654 600mg vs Placebo -3.8-9.8, 2.2 0.2125 600mg + 450mg vs Placebo -0.9-5.9, 4.2 0.7362 300mg + 450mg vs Placebo -1.5-6.3, 3.3 0.5363 300mg vs Placebo -5.1-10.3, 0.1 0.0564 300mg + 100mg vs Placebo -3.5-8.2, 1.2 0.1407 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 21
Supplemental Table 18: Summary of deamidated gliadin peptide-igg serology in the (week 12) Modified Intent-to-Treat population DGP-IgG (U) Baseline Treatment Group (N=419) Placebo (N=128) 100 mg (N=49) 300 mg (N=80) 450 mg (N=42) 600 mg (N=82) 900 mg (N=38) Number of Patients 128 49 80 42 82 38 Mean (SD) 25.0 (33.13) 24.9 (33.44) 23.7 (31.37) 17.9 (27.78) 26.4 (34.90) 17.6 (27.94) Median 7.0 8.0 7.0 5.5 8.0 5.0 Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Number of Patients 128 49 80 42 82 38 Mean (SD) 25.1 (34.19) 24.7 (32.36) 22.8 (30.23) 16.8 (25.70) 24.7 (33.57) 18.1 (28.37) Median 7.0 7.0 7.0 6.0 7.5 5.5 Min, Max 1, 100 2, 100 1, 100 1, 100 1, 100 1, 100 Change from Baseline at Number of Patients 128 49 80 42 82 38 Mean (SD) 0.2 (11.08) -0.3 (13.90) -1.0 (6.86) -1.1 (7.47) -1.6 (6.88) 0.5 (4.86) Median 0.0 0.0 0.0 0.0 0.0 0.0 Min, Max -31, 83-22, 85-23, 22-37, 12-40, 15-16, 16 p-value 0.8548 0.8943 0.2019 0.3577 0.0344 0.5302 DGP = deamidated gliadin peptide 22
Supplemental Table 19: Analysis of covariance of the change from baseline in deamidated gliadin peptide-igg (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgG (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 126 25.2 126 0.2-1.8, 2.2 100 mg 48 25.4 48-0.3-4.4, 3.8 300 mg 76 24.7 76-1.0-2.6, 0.6 450 mg 39 15.9 39-0.9-3.4, 1.6 600 mg 77 27.3 77-1.6-3.2, -0.1 900 mg 38 17.6 38 0.5-1.1, 2.1 Treatment Effect 2 600mg + 900mg vs Placebo -0.9-3.4, 1.5 0.4525 600mg vs Placebo -1.7-4.4, 0.9 0.1992 600mg + 450mg vs Placebo -1.7-4.1, 0.7 0.1754 300mg + 450mg vs Placebo -1.4-3.9, 1.0 0.2459 300mg vs Placebo -1.3-3.9, 1.4 0.3531 300mg + 100mg vs Placebo -0.9-3.2, 1.5 0.4627 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 23
DGP-IgG (U) Baseline Supplemental Table 20: Summary of deamidated gliadin peptide-igg serology in the treatment extension (week 24) MITT population Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients 30 14 23 12 16 12 900 mg (N=12) Mean (SD) 25.8 (33.20) 17.0 (29.59) 35.6 (39.98) 10.1 (11.90) 33.0 (40.77) 10.1 (16.97) Median 11.5 7.0 8.0 5.0 9.0 3.5 Min, Max 1, 100 2, 100 1, 100 2, 44 1, 100 1, 54 Number of Patients 30 14 23 12 15 12 Mean (SD) 27.9 (35.83) 15.5 (27.71) 33.8 (37.69) 11.3 (15.40) 29.5 (39.26) 12.1 (20.61) Median 11.0 5.5 6.0 4.5 10.0 3.5 Min, Max 1, 100 2, 100 1, 100 1, 56 1, 100 1, 59 Change from Baseline at Number of Patients 30 14 23 12 15 12 Mean (SD) 2.1 (15.60) -1.5 (4.91) -1.7 (7.62) 1.2 (3.76) 0.7 (2.47) 2.0 (4.65) Median 0.0-0.5 0.0 0.0 0.0 0.5 Min, Max -10, 83-17, 6-21, 16-2, 12-2, 7-1, 16 p-value 0.4740 0.2737 0.2857 0.3057 0.3134 0.1645 Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) 23.5 (29.78) 18.4 (30.31) 33.4 (36.83) 12.7 (18.29) 31.8 (36.55) 10.2 (16.89) Median 9.0 5.5 6.0 5.0 11.5 3.0 Min, Max 1, 100 1, 99 1, 100 1, 57 1, 100 1, 55 Change from Baseline at Week 24 Number of Patients 30 14 23 12 16 12 Mean (SD) -2.3 (12.86) 1.4 (4.88) -2.2 (13.48) 2.6 (10.11) -1.3 (16.97) 0.1 (1.16) Median -1.0 0.0 0.0-1.0 0.0 0.0 Min, Max -34, 38-3, 16-34, 25-8, 31-46, 38-2, 2 p-value 0.3354 0.3168 0.4474 0.3951 0.7723 0.8088 DGP = deamidated gliadin peptide 24
Supplemental Table 21: Analysis of covariance of the change from baseline in the deamidated gliadin peptide-igg treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgG (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo 30 25.8 30 2.1-3.8, 7.9 100 mg 14 17.0 14-1.5-4.3, 1.3 300 mg 23 35.6 23-1.7-5.0, 1.6 450 mg 12 10.1 12 1.2-1.2, 3.6 600 mg 16 33.0 15 0.7-0.7, 2.0 900 mg 12 10.1 12 2.0-1.0, 5.0 Treatment Effect 2 600mg + 900mg vs Placebo -0.8-5.9, 4.2 0.7391 600mg vs Placebo -1.2-7.2, 4.7 0.6870 600mg + 450mg vs Placebo -1.6-6.6, 3.5 0.5367 300mg + 450mg vs Placebo -2.6-7.4, 2.2 0.2799 300mg vs Placebo -3.3-8.6, 1.9 0.2107 300mg + 100mg vs Placebo -3.6-8.3, 1.0 0.1264 1 Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 25
Supplemental Table 22: Analysis of covariance summary of non-stool symptoms by stratum Measure Abdominal pain frequency Change from Baseline to Week 6 Change from Baseline to Overall Sero-Negative Sero-Positive Overall Sero-Negative Sero-Positive A600+900 (=0.010) A600 (p=0.039) A900 (p=0.034) Abdominal pain severity A600+900 (=0.008) A600 (p=0.026) A900 (p=0.038) Bloating frequency A300 (p=0.049) Bloating severity A600+900 (p=0.007) A600 (p=0.040) A900 (p=0.021) A600+900 (=0.007) A600 (p=0.040) A900 (p=0.023) Nausea frequency A900 (p=0.022) A100 (p=0.043) Nausea severity Tiredness frequency A600 (P-0.049) A600+900 (=0.018) A600 (p=0.038) A300 (p=0.015) A300+100 (p=0.022) A600 (p=0.012) Tiredness severity A600+900 (p=0.014) A600 (p=0.028) A600+450 (p=0.025) A600+900 (p=0.026) A300 (p=0.046) A300+100 (p=0.037) A600+900 (=0.009) A600 (p=0.002) Overall non-stool specific frequency Overall non-stool specific activity A600+900 (p=0.007) A600 (p=0.029) A900 (p=0.032) The pattern suggests that higher doses (600 mg and 900 mg) in the most symptomatic patients may be able to overcome the trial effect A600+900 (=0.007) A600 (p=0.026) A900 (p=0.034) 26
Supplemental Table 23: Responder analysis of change from baseline in Celiac Disease Symptom Diary frequency and severity scores based on Patient Global Impression Symptoms responder definitions at week 12 CDSD Domain Change Mean (SD) Much Deterioration (n=6) Deterioration (n=33) No Change (n=128) Improvement (n=109) Much Improvement (n=98) P value 1 Diarrhea frequency 1.57 (1.60) 0.46 (2.11) -0.13 (1.95) -0.25 (1.69) -0.97 (2.29) <0.001 Diarrhea severity 3.0 (2.7) 1.4 (4.8) -0.7 (5.4) -0.8 (4.1) -2.6 (5.9) <0.001 CSBM frequency -1.19 (2.18) -0.23 (2.04) 0.05 (1.48) -0.07 (1.87) -0.05 (2.52) 0.687 CSBM severity -14.0 (31.3) 1.2 (24.2) 1.1 (16.8) -1.0 (18.0) 0.6 (25.0) 0.532 Abdominal pain frequency 1.13 (1.24) -0.38 (1.79) -0.71 (1.93) -0.90 (2.08) -2.02 (2.48) <0.001 Abdominal pain severity 3.9 (4.8) -0.4 (7.0) -2.6 (8.9) -3.6 (9.6) -8.9 (10.7) <0.001 Bloating frequency 0.77 (2.91) -0.01 (1.89) -0.56 (1.89) -0.96 (2.10) -1.95 (2.61) <0.001 Bloating severity 10.6 (10.1) 1.5 (11.2) -2.8 (11.5) -6.3 (12.1) -13.1 (15.3) <0.001 Nausea frequency 0.75 (0.52) 0.21 (1.17) -0.12 (1.58) -0.62 (1.52) -1.10 (1.86) <0.001 Nausea severity 3.9 (3.2) 0.6 (6.7) -0.8 (8.0) -3.1 (8.4) -6.5 (10.1) <0.001 Tiredness frequency 0.58 (1.16) -0.53 (1.65) -0.83 (1.83) -0.90 (2.24) -2.30 (2.87) <0.001 Tiredness severity 3.1 (2.7) -3.2 (9.1) -4.9 (11.8) -6.1 (13.4) -14.3 (17.6) <0.001 Overall non-stool specific gastrointestinal frequency Overall non-stool specific gastrointestinal activity 0.44 (2.60) -0.26 (1.78) -0.71 (2.12) -1.19 (2.09) -2.14 (2.52) <0.001 18.4 (13.7) 1.7 (15.6) -6.2 (20.1) -13.0 (21.5) -28.4 (27.4) <0.001 1 p value derived from one-way ANOVA F test. CDSD = Celiac Disease Symptom Diary; CSBM = complete spontaneous bowel movement 27
Supplemental Table 24: Analysis of covariance predicting change from baseline to week 12 in Impact of Celiac Disease Symptoms Questionnaire overall score Treatment Group LS-Mean SE 95% CI P value Placebo -2.18 0.22 (-2.62, -1.74) <0.001 ALV003 100 mg (A100) -2.89 0.37 (-3.61, -2.16) <0.001 ALV003 300 mg (A300) -2.52 0.30 (-3.11, -1.92) <0.001 ALV003 450 mg (A450) -2.75 0.41 (-3.55, -1.95) <0.001 ALV003 600 mg (A600) -2.43 0.28 (-2.98, -1.88) <0.001 ALV003 900 mg (A900) -2.46 0.43 (-3.31, -1.61) <0.001 Seronegative at baseline -2.42 0.17 (-2.75, -2.08) <0.001 Seropositive at baseline -2.50 0.19 (-2.87, -2.12) <0.001 Comparisons: (A600+A900) Placebo -0.27 0.34 (-0.94, 0.40) 0.432 A600 Placebo -0.26 0.36 (-0.96, 0.45) 0.476 (A600+A450) Placebo -0.41 0.33 (-1.07, 0.24) 0.216 (A300+A450) Placebo -0.46 0.34 (-1.12, 0.21) 0.180 A300 Placebo -0.34 0.38 (-1.08, 0.40) 0.367 (A300+A100) Placebo -0.53 0.33 (-1.17, 0.12) 0.108 A900 Placebo -0.28 0.49 (1.24, 0.68) 0.563 A450 Placebo -0.57 0.47 (-1.49, 0.34) 0.220 A100 Placebo -0.71 0.43 (-1.56, 0.14) 0.099 ANCOVA model adjusted for baseline score and serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 28
Supplemental Table 25: Analysis of covariance predicting change from baseline to week 24 in Impact of Celiac Disease Symptoms Questionnaire overall score Treatment Group LS-Mean SE 95% CI P value Placebo -2.58 0.38 (-3.34, -1.82) <0.001 ALV003 100 mg (A100) -2.63 0.54 (-3.71, -1.55) <0.001 ALV003 300 mg (A300) -2.32 0.43 (-3.17, -1.47) <0.001 ALV003 450 mg (A450) -3.40 0.59 (-4.56, -2.24) <0.001 ALV003 600 mg (A600) -3.52 0.51 (-4.52, -2.51) <0.001 ALV003 900 mg (A900) -2.34 0.59 (-3.51, -1.16) <0.001 Seronegative at baseline -2.77 0.25 (-3.27, -2.26) <0.001 Seropositive at baseline -2.69 0.32 (-3.31, -2.06) <0.001 Comparisons: (A600+A900) Placebo -0.35 0.55 (-1.44, 0.74) 0.524 A600 - Placebo -0.94 0.63 (-2.20, 0.32) 0.142 (A600+A450) Placebo -0.88 0.54 (-1.96, 0.20) 0.108 (A300+A450) Placebo -0.28 0.53 (-1.34, 0.77) 0.594 A300 Placebo 0.26 0.58 (-0.90, 1.41) 0.661 (A300+A100) Placebo 0.10 0.52 (-0.93, 1.13) 0.846 A900 Placebo 0.24 0.71 (-1.17, 1.65) 0.737 A450 Placebo -0.82 0.70 (-2.21, 0.57) 0.242 A100 Placebo -0.05 0.66 (-1.37, 1.26) 0.936 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 29
Supplemental Table 26: Analysis of covariance predicting change from week 12 in Short Form SF-12v2 Health Survey: Physical component score Treatment Group LS-Mean SE 95% CI P value Placebo 3.9 2.0 (0.0, 7.8) 0.048 ALV003 100 mg (A100) 8.0 3.3 (1.5, 14.4) 0.016 ALV003 300 mg (A300) 9.6 2.7 (4.3, 14.8) <0.001 ALV003 450 mg (A450) 10.4 3.6 (3.3, 17.6) 0.004 ALV003 600 mg (A600) 9.5 2.5 (4.6, 14.4) <0.001 ALV003 900 mg (A900) 3.8 3.8 (-3.7, 11.3) 0.320 Seronegative at baseline 6.6 1.5 (3.6, 9.5) <0.001 Seropositive at baseline 7.9 1.7 (4.6, 11.2) <0.001 Comparisons: (A600+A900) Placebo 2.8 3.0 (-3.2, 8.7) 0.363 A600 - Placebo 5.6 3.2 (-0.7, 11.9) 0.079 (A600+A450) Placebo 6.1 3.0 (0.2, 11.9) 0.042 (A300+A450) Placebo 6.1 3.0 (0.02, 12.0) 0.044 A300 Placebo 5.6 3.3 (-0.9, 12.2) 0.091 (A300+A100) Placebo 4.8 2.9 (-0.8, 10.5) 0.095 A900 Placebo -0.1 4.3 (-8.6, 8.4) 0.979 A450 Placebo 6.5 4.1 (-1.6, 14.7) 0.116 A100 Placebo 4.0 3.8 (-3.5, 11.6) 0.290 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 30
Supplemental Table 27: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-12v2 Health Survey: physical component score Treatment Group LS-Mean SE 95% CI P value Placebo 8.2 3.4 (1.5, 15.0) 0.017 ALV003 100 mg (A100) 5.2 4.9 (-4.5, 14.9) 0.288 ALV003 300 mg (A300) 4.5 3.8 (-2.9, 12.2) 0.224 ALV003 450 mg (A450) 15.1 5.2 (4.7, 25.5) 0.005 ALV003 600 mg (A600) 13.6 4.6 (4.6, 22.7) 0.003 ALV003 900 mg (A900) 8.9 5.3 (-1.5, 19.4) 0.093 Seronegative at baseline 11.3 2.3 (6.7, 15.8) <0.001 Seropositive at baseline 4.9 2.8 (-0.7, 10.5) 0.088 Comparisons: (A600+A900) Placebo 3.0 4.9 (-6.6, 12.7) 0.534 A600+Placebo 5.4 5.7 (-5.9, 16.7) 0.345 (A600+A450) Placebo 6.1 4.9 (-3.6, 15.8) 0.213 (A300+A450) Placebo 1.6 4.7 (-7.7, 11.0) 0.732 A300 Placebo -3.6 5.1 (-13.7, 6.5) 0.480 (A300+A100) Placebo -3.3 4.5 (-12.4, 5.7) 0.469 A900 Placebo 0.7 6.3 (-11.8, 13.1) 0.914 A450 Placebo 6.8 6.3 (-5.6, 19.3) 0.278 A100 Placebo -3.0 5.9 (-14.8, 8.7) 0.609 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 31
Supplemental Table 28: Analysis of covariance predicting change from baseline to week 12 in Short Form SF-12v2 Health Survey: mental component score Treatment Group LS-Mean SE 95% CI P value Placebo 5.9 1.5 (3.0, 8.7) <0.001 ALV003 100 mg (A100) 9.4 2.4 (4.7, 14.1) <0.001 ALV003 300 mg (A300) 7.4 2.0 (3.5, 11.2) <0.001 ALV003 450 mg (A450) 9.7 2.7 (4.4, 14.9) <0.001 ALV003 600 mg (A600) 10.5 1.8 (6.9, 14.1) <0.001 ALV003 900 mg (A900) 9.7 2.8 (4.2, 15.3) <0.001 Seronegative at baseline 6.5 1.1 (4.4, 8.7) <0.001 Seropositive at baseline 10.3 1.2 (7.8, 12.7) <0.001 Comparisons: (A600+A900) Placebo 4.2 2.2 (-0.1, 8.6) 0.057 A600+Placebo 4.6 2.3 (0.0, 9.2) 0.048 (A600+A450) Placebo 4.2 2.2 (-0.1, 8.5) 0.055 (A300+A450) Placebo 2.6 2.2 (-1.7, 7.0) 0.234 A300 Placebo 1.5 2.4 (-3.3, 6.3) 0.543 (A300+A100) Placebo 2.5 2.1 (-1.7, 6.7) 0.241 A900 Placebo 3.8 3.2 (-2.4, 10.1) 0.226 A450 Placebo 3.8 3.0 (-2.2, 9.8) 0.214 A100 Placebo 3.5 2.8 (-2o, 9.0) 0.213 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 32
Supplemental Table 29: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-12v2 Health Survey: mental component score Treatment Group LS-Mean SE 95% CI P value Placebo 10.9 2.8 (5.3, 16.4) <0.001 ALV003 100 mg (A100) 9.7 4.0 (1.7, 17.7) 0.018 ALV003 300 mg (A300) 12.4 3.1 (6.2, 18.6) <0.001 ALV003 450 mg (A450) 15.7 4.3 (7.1, 24.3) <0.001 ALV003 600 mg (A600) 15.4 3.8 (7.9, 23.0) <0.001 ALV003 900 mg (A900) 10.6 4.4 (2.0, 19.3) 0.017 Seronegative at baseline 12.9 1.9 (9.1, 16.6) <0.001 Seropositive at baseline 11.4 2.3 (6.7, 16.0) <0.001 Comparisons: (A600+A900) Placebo 2.1 4.0 (-5.8, 10.1) 0.593 A600+Placebo 4.5 4.7 (-4.8, 13.8) 0.336 (A600+A450) Placebo 4.7 4.0 (-3.3, 12.6) 0.244 (A300+A450) Placebo 3.2 3.9 (-4.5, 10.9) 0.413 A300 Placebo 1.5 4.2 (-6.8, 9.9) 0.715 (A300+A100) Placebo 0.2 3.8 (-7.4, 7.7) 0.964 A900 Placebo -0.2 5.2 (-10.6, 10.1) 0.965 A450 Placebo 4.8 5.2 (-5.4, 15.1) 0.351 A100 Placebo -1.2 4.9 (-11.0, 8.6) 0.809 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 33
Supplemental Table 30: Analysis of covariance predicting change from baseline to week 12 in Short Form SF-6D Health Survey: utility index Treatment Group LS-Mean SE 95% CI P value Placebo 0.044 0.010 (0.025, 0.64) <0.001 ALV003 100 mg (A100) 0.065 0.017 (0.032, 0.098) <0.001 ALV003 300 mg (A300) 0.069 0.014 (0.042, 0.096) <0.001 ALV003 450 mg (A450) 0.098 0.018 (0.061, 0.134) <0.001 ALV003 600 mg (A600) 0.075 0.013 (0.050, 0.100) <0.001 ALV003 900 mg (A900) 0.050 0.019 (0.011, 0.088) 0.011 Seronegative at baseline 0.054 0.008 (0.039, 0.069) <0.001 Seropositive at baseline 0.074 0.009 (0.057, 0.091) <0.001 Comparisons: (A600+A900) Placebo 0.018 0.015 (-0.012, 0.048) 0.245 A600+Placebo 0.031 0.016 (-0.001, 0.062) 0.059 (A600+A450) Placebo 0.042 0.015 (0.012, 0.071) 0.006 (A300+A450) Placebo 0.039 0.015 (0.009, 0.069) 0.011 A300 Placebo 0.024 0.017 (-0.009, 0.058) 0.150 (A300+A100) Placebo 0.023 0.015 (-0.006, 0.051) 0.125 A900 Placebo 0.005 0.022 (-0.038, 0.048) 0.812 A450 Placebo 0.053 0.021 (0.012, 0.094) 0.012 A100 Placebo 0.021 0.019 (-0.018, 0.059) 0.288 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 34
Supplemental Table 31: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-6D Health Survey: utility index Treatment Group LS-Mean SE 95% CI P value Placebo 0.075 0.017 (0.040, 0.109) <0.001 ALV003 100 mg (A100) 0.102 0.025 (0.053, 0.151) <0.001 ALV003 300 mg (A300) 0.046 0.020 (0.007, 0.085) 0.021 ALV003 450 mg (A450) 0.116 0.027 (0.063, 0.170) <0.001 ALV003 600 mg (A600) 0.089 0.023 (0.042, 0.135) <0.001 ALV003 900 mg (A900) 0.053 0.027 (-0.001, 0.106) 0.054 Seronegative at baseline 0.065 0.012 (0.042, 0.088) <0.001 Seropositive at baseline 0.095 0.014 (0.066, 0.123) <0.001 Comparisons: (A600+A900) Placebo -0.004 0.025 (-0.053, 0.045) 0.869 A600+Placebo 0.014 0.029 (-0.043 0.071) 0.631 (A600+A450) Placebo 0.028 0.025 (-0.021, 0.077) 0.262 (A300+A450) Placebo 0.007 0.024 (-0.041, 0.054) 0.787 A300 Placebo -0.029 0.026 (-0.081, 0.024) 0.279 (A300+A100) Placebo -0.001 0.024 (-0.047, 0.046) 0.980 A900 Placebo -0.022 0.032 (-0.086, 0.042) 0.493 A450 Placebo 0.042 0.032 (-0.022, 0.105) 0.194 A100 Placebo 0.027 0.030 (-0.033, 0.088) 0.366 ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 35
Supplemental Table 32: Summary of frequently reported adverse events by system organ class in the safety (week 12) and treatment extension (week 24) populations Treatment Group Gastrointestinal Disorders (n, %) Placebo 100 mg 300 mg 450 mg 600 mg 900 mg Safety Population 46 (31.1%) 12 (24.0%) 29 (29.9%) 15 (31.3%) 27 (27.3%) 15 (31.9%) Treatment Extension Population Infections (n, %) 12 (36.4%) 2 (14.3%) 6 (24.0%) 1 (8.3%) 7 (36.8%) 4 (30.8%) Safety Population 36 (24.3%) 7 (14.0%) 17 (17.5%) 7 (14.6%) 27 (27.3%) 7 (14.9%) Treatment Extension Population 11 (33.3%) 4 (28.6%) 4 (16.0%) 2 (16.7%) 9 (47.4%) 2 (15.4%) 36