EXECUTIVE SUMMARY. Date of Report: 25-Mar Database as of: 05-Mar-2008

Transcription

1 EXECUTIVE SUMMARY Date of Report: 25-Mar-2008 Database as of: 05-Mar-2008 Title of Study: Protocol : A Phase II, Multi-center, Randomized, Double-Blind, Placebo Controlled, Dose-Response Study to Evaluate the Safety and Clinical Efficacy of Two Different Doses of () Administered Intravenously to Japanese Subjects with Active Rheumatoid Arthritis While Receiving Methotrexate Investigators/Study Centers and Countries: 42 sites in Japan Publication (reference): None Study Period (First Patient First Visit to Last Patient Last Visit): 15-Jun-2006 to 29-Nov-2007 Study Phase: II Research Hypothesis: combined with methotrexate will demonstrate an efficacy dose response in Japanese subjects with active RA as assessed by ACR 20 response rates after six months (Day 169) of treatment similar to the efficacy dose response relationship previously demonstrated population in a worldwide trial (Study IM101100). Primary Objective: To demonstrate the efficacy dose response of abatacept (2 and 10 mg/kg) compared with placebo on a common background of methotrexate after six months (Day 169) of treatment in Japanese subjects with active RA and an inadequate clinical response to Methotrexate as assessed by ACR 20. Secondary Objective: 1) Assess dose response relationship of ACR20 after six months (Day 169) of treatment with previously demonstrated in a worldwide trial (IM101100). 2) Compare the efficacy of two different doses of abatacept with placebo, on a common background of MTX, after six months (Day 169) of treatment in subjects with active RA as assessed by ACR20, ACR 50 and ACR 70. 3) Compare ACR 20, ACR 50 and ACR 70 response rates over time among the treatment groups. 4) Assess the time of onset of action and time to maximal response in subjects receiving abatacept in combination with methotrexate. 5) Assess the improvement in physical function as assessed by the Health Assessment Questionnaire (HAQ) in subjects receiving abatacept in combination with methotrexate. 6) Assess the change of subject s health-related quality of life, as measured by the SF-36 questionnaire, in subjects receiving abatacept in combination with methotrexate. 7) Assess disease activity, as measured by Disease Activity Score-28 (DAS-28), in subjects receiving abatacept in combination with methotrexate. 8) Assess the safety of chronic use of abatacept in subjects receiving abatacept in combination with methotrexate. 9) Assess the immunogenicity of abatacept in subjects receiving abatacept in combination with methotrexate. 1

2 10) Assess changes in rheumatoid factor (RF), biomarkers (CRP, sil-2r) and cytokine levels (TNFα, IL- 6, ICAM-1 and E-selectin) in subjects receiving abatacept in combination with methotrexate.] 11) Assess the pharmacokinetics of abatacept. 12) Assess the pharmacokinetic/drug effect or pharmacodynamic relationship. Study Design: Randomized (1:1:1), double-blind, placebo controlled, parallel dosing, multi-center, doseresponse study. Subjects were randomized to 1 of 3 dosing arms: abatacept at 2 mg/kg, abatacept at 10 mg/kg, or placebo, all on a background of methotrexate. Current anti-rheumatic treatment Methotrexate Monotherapy Methotrexate and DMARDs or Biologics Preliminary Registration After obtaining written consent, preliminary registration was conducted. Formal Registration After obtaining written consent, Formal registration was conducted. After WASHOUT period of DMARD (except methotrexate), Formal registration was conducted. Visit Schedule Day 1 Day 15 Day 29 Every 28 days until Day 169 Dosing started Day 1 and occurred at every scheduled visit up to and including Day 141. RANDOMIZED TO EITHER: 1) 2mg/kg + methotrexate 2) 10 mg/kg + methotrexate 3) Placebo + methotrexate Study Population: Japanese subjects with active rheumatoid arthritis and an inadequate clinical response to Methotrexate while receiving Methotrexate. Key inclusion/exclusion criteria: 1) Diagnosis of RA and RA functional classes I, II, or III; 2) Treated with methotrexate (6-8 mg weekly) for at least 12 weeks, at a stable dose for 28 days prior to formal registration; 3) Had the following criteria for disease activity at formal registration: 10 or more swollen joints (66 joint count), 12 or more tender joint counts (68 joint counts) and CRP level 1 mg/dl (10 mg/l); 4) Men and Women, at least 20 years of age. Test Product, Dose and Mode of Administration, Duration of Treatment: All doses of study medication were reconstituted with 5% Dextrose Injection or 0.9% Sodium Chloride, and administered in a fixed volume of 100 ml at a constant rate over approximately 30 minutes. Infusion doses were based upon the subject s body weight obtained from the formal registration screening visit and were not to be modified throughout the remainder of the study. Subjects received doses of study medication at every treatment period visit (Days 1, 15, 29, 57, 85, 113, and 141) with the exception of Day 169. During study period, increases in methotrexate and oral corticosteroids (stable dose; at 10 mg prednisone-equivalent daily or less) were not permitted. Decreases in these doses, only if due to toxicity were allowed. Batch numbers were 5D01057 and 6F Reference Therapy, Dose and Mode of Administration, Duration of Treatment (Batch Numbers): Placebo and methotrexate cohort. Mode of administration and duration of treatment are described as above. Batch numbers were 6E10010 and 6K

3 Criteria for Evaluation: Efficacy Measures: ACR response, ACR core data set, HAQ, SF-36 and DAS28 Safety Measures: Seriousness, Causal relationship to the study drug, Outcome, Action taken with respect to investigational product administration, Treatment required. Pharmacokinetic Measures: Pharmacokinetic parameters including CLT, Cmin and AUC, and the abatacept concentration versus time data. The pharmacokinetic evaluations will was to be assessed by population pharmacokinetics. Pharmcodynamic Measures: RF, biomarkers (CRP, sil-2r) and cytokine levels (TNFα, IL-6, ICAM-1 and E-selectin) Immunogenicity Measures: anti-abatacept antibody and immunogenicity response (positive/negative) Statistical Methods: Based on observed ACR20 proportions from study IM101100, 57 subjects per treatment yields an 80% power to detect a linear trend in a dose response curve at the 5% level. Sample size was adjusted for a possible 5% drop out rate (n= 3) from formal registration to first treatment;, 60 subjects per treatment were planned. Efficacy: The primary efficacy analysis was to test a non-zero slope of the dose response using the Cochran-Armitage Chi square trend test for proportions. If the slope was statistically significant at the 0.05 level, a sequential testing procedure would be employed to preserve the overall alpha level at 5%. First, a Chi square test was used to compare the data for the 10 mg/kg group on Day 169 with the data for the placebo group at the 0.05 level. If this was significant, the data for the 2 mg/kg group would be compared with the placebo group at the 0.05 level. Descriptive statistics were provided for all clinical variables for each dosing arm. Differences in ACR 20, ACR 50 and ACR 70 response rates between each abatacept arm and placebo were summarized using point estimates and 95% confidence intervals. The results will also be assessed relative to foreign data in study IM and will be comprehensively evaluated to determine the extrapolatability of the foreign clinical data to the Japanese. Safety: Summary statistics were tabulated. Frequency distribution and individual listing of all adverse events were generated according to the arm. Pharmacokinetics: Serum abatacept concentration and Pharmacokinetic parameters were summarized using descriptive statistics by arm. The concentration versus time data was used to assess a population pharmacostatistical model. The results of the phamacokinetics will be prepared and reported separately. Immunogenicity: The distribution of immunogenicity variables were summarized using descriptive statistics by doses. The results of the immunogenicity will be prepared and reported separately. 3

4 RESULTS Subject Disposition: Most of all subjects in the abatacept groups completed 169 days of treatment compared with the placebo group: 98.4 % (61/62) of those randomized to the 10 mg/kg group, 98.5 % (66/67) randomized to the 2 mg/kg group and 86.4 % (57/66) randomized to the placebo group (Table. 1). Most of the patients who discontinued were in the placebo group, and the main reason for study discontinuation was lack of efficacy (n=3) and Withdrawal offer from subject (n=3). Two patients in the placebo group discontinued for adverse events, while none were reported in the active groups. Table 1: Subject Disposition and Reasons for discontinuation 10 mg/kg 2 mg/kg Placebo N=62 N=67 N=66 Treated 61 (98.4) 67 (100.0) 66 (100.0) Completed 61 (98.4) 66 (98.5) 57 (86.4) Discontinued 1 (1.6) 1 (1.5) 9 (13.6) Main Reasons for Discontinuation: Withdrawal offer from subject (4.5) Lack of efficacy (4.5) Adverse event (3.0) Other 1 (1.6) a 0 1 (1.5) Not to meet the Inclusion/Exclusion criteria 0 1 (1.5) b 0 Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: Randomized subjects. a The subject discontinued before first dosing of abatacept. b The subject was confirmed not to meet the Inclusion/Exclusin criteria after the first dosing of abatacept. 4

5 Subject Demographics: Most subjects were females, with a mean age of about 53, and mean disease duration of RA of approximately 7 to 8 years. Baseline demographics and characteristics of disease activity (tender, swollen joint counts, physical function, and C-Reactive Protein [CRP]) and dosages of methotrexate and oral corticosteroids were similar among abatacept and placebo groups (Table 2). Table 2: Baseline Characteristics 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 Age (yrs) - Mean (SD) 53.4 (11.3) 52.5 (11.1) 53.4 (12.0) - Range 22, 74 22, 78 27, 79 Weight (kg) - Mean (SD) 53.8 (8.0) 56.2 (10.1) 57.7 (9.6) - Range 38.0, , , 85.1 Gender, Females, n (%) 49 (80.3) 57 (85.1) 52 (78.8) Duration of RA (yrs) - Mean (SD) 7.4 (5.7) 8.5 (9.0) 7.3 (6.2) Tender Joints - Mean (SD) 21.8 (9.3) 21.0 (8.2) 21.6 (8.2) Swollen Joints - Mean (SD) 16.6 (6.7) 17.6 (6.5) 17.5 (6.1) Physical Function - Mean (SD) (HAQ 0-3) 1.33 (0.59) 1.24 (0.69) 1.50 (0.73) CRP mg/dl - Mean (SD) 3.40 (2.74) 2.98 (2.37) 3.39 (2.28) Methotrexate (mg/wk) a - n Mean (SD) 7.11 (1.00) 7.11 (0.98) 7.26 (0.96) Oral Corticosteroids (mg/day) - n Mean (SD) 5.68 (2.21) 5.81 (2.45) 5.58 (2.47) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. a MTX dose was defined within mg/week by protocol. 5

6 Efficacy results: Signs and Symptoms: Primary efficacy variable: abatacept 2 or 10 mg/kg or placebo combined with methotrexate (MTX) showed a dose response between the 2 active groups, and the primary endpoint ACR 20 was statistically significant at Day 169 (P < 0.001) (fig. 1). For the abatacept 10 mg/kg (plus MTX), statistically significant differences from the placebo (MTX alone) were seen for ACR 20, 50 and 70 rates at Days 169 (p < 0.001). These responses were lower in the abatacept 2 mg/kg group, but they were still statistically significant. There was consistency in the effectiveness of active treatment (particularly at the higher 10 mg/kg doses) over placebo for the ACR 20, 50 and 70 responses at Day169. The response was detected as early as day 15, and the 10 mg/kg group always showed a higher response rate than the placebo arm with the ACR 20 response (Figure. 2). In the 2 mg/kg arm, the ACR 20 appears to plateau around Day 90, and then tends to decline slightly. In the 10 mg/kg group compared with the placebo group, statistically significant improvements in ACR 20, ACR 50, and ACR 70 responses were observed as early as Day 29, 29 and 85, respectively (The 95% interval for the difference in response, relative to placebo, did not contain zero at the 10 mg/kg dose level) (Figure. 2, 3, and 4). Mean percentage improvements in all ACR component (tender and swollen joint counts, physical function (HAQ), pain, subject global assessment, physician global assessment, CRP) at Day 169 were significantly higher for the 10 mg/kg group relative to improvements for the placebo group (P < 0.001). There was consistency in the effectiveness of active treatment (particularly at the higher 10 mg/kg doses) over placebo for the components of the ACR core data set at Day169. Regarding the DAS 28 (CRP), more subjects treated with abatacept 10 mg/kg showed a response (86.9% versus 28.8%), had low disease activity (54.1 % versus 15.2 %) and were in remission (37.7 % versus 7.6 %) compared to placebo at Day 169 (Table. 4). The 2 mg/kg group showed an intermediate response in all categories. 6

7 Figure 1: ACR Responses at Day 169 with 95 Percent Confidence Intervals Table 3: ACR Response Rates at Day 169 ACR mg/kg 2 mg/kg Placebo N=61 N=67 N=66 n (%) 47 (77.0) 42 (62.7) 14 (21.2) Trend test a < Estimate of the difference with respect to placebo (95% CI) (41.4, 70.3) (26.3, 56.7) P-value b <.001 < ACR 50 n (%) 28 (45.9) 25 (37.3) 4 (6.1) Trend test a < Estimate of the difference with respect to placebo (95% CI) (26.1, 53.6) (18.3, 44.2) P-value b <.001 <

8 Table 3: ACR Response Rates at Day 169 ACR mg/kg 2 mg/kg Placebo n (%) 13 (21.3) 11 (16.4) 0 Trend test a < Estimate of the difference with respect to placebo (95% CI) (11.0, 31.6) (7.5, 25.3) P-value b < Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. Subjects who discontinued the study due to lack of efficacy were considered ACR non-responders at all subsequent time points. For all subjects who discontinued for other reasons, their last ACR response was carried forward. a Cochran-Armitage Trend Test b Comparison of abatacept vs. placebo Chi-square test 8

9 Figure 2: Summary of ACR 20 Response by Visit Figure 3: Summary of ACR 50 Response by Visit 9

10 Figure 4: Summary of ACR 70 Response by Visit Table 4: DAS28 (CRP) Subjects with Improvement - n (%) (DAS 28 change >= 1.2) Subjects with Low Disease Activity - n (%) (DAS 28 <= 3.2) Subjects in Remission - n (%) (DAS 28 < 2.6) 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 53 (86.9) 44 (65.7) 19 (28.8) 33 (54.1) 28 (41.8) 10 (15.2) 23 (37.7) 17 (25.4) 5 (7.6) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. Change from baseline = (Post baseline value - Baseline) n is the number of subjects with both baseline and post-baseline measure at any given time point (LOCF) ANCOVA model: change = pre treatment 10

11 Physical Function (HAQ): Adjusted mean percent improvements from baseline for abatacept 10 mg/kg, 2 mg/kg and placebo were 40.3 %, 26.9 % and 7.2 %, respectively at Day 169 (Table. 5). A greater mean improvement from baseline was observed for the HAQ disability index for the abatacept 10 mg/kg group compared with the placebo group and was statistically significant (p < 0.001). At Day 169, more subjects in the abatacept 10 mg/kg group compared with the placebo group (60.7 % vs %), achieved a HAQ response that was clinically meaningful (defined as an improvement of at least 0.3 units in the HAQ disability index) (Table. 6). Table 5: Patient Assessment of Physical Function (HAQ) -Treatment Comparisons of Mean Percent Changes from Baseline (B/L) 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 n B/L Mean (SD) 1.4 (0.6) 1.3 (0.6) 1.6 (0.7) Post B/L Mean (SD) 0.8 (0.6) 0.9 (0.7) 1.4 (0.7) % Improve from B/L Mean (SE) 40.2 (5.2) 26.5 (6.0) 7.7 (5.5) % Improve from B/L Adjusted 40.3 (5.7) 26.9 (5.6) 7.2 (5.6) Mean (SE) Estimate of the difference with respect to placebo (95% CI) (17.3, 49.0) (4.0, 35.4) p-value < Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. % Change from baseline = (Baseline - Post baseline value) / baseline value x 100 n is the number of subjects with both baseline and post-baseline measure at any given time point ANCOVA model: % change = pre treatment 11

12 Table 6: Proportion of Subjects with Clinically Meaningful HAQ Responses at Day mg/kg 2 mg/kg Placebo N=61 N=67 N=66 n (%) 37 (60.7) 33 (49.3) 16 (24.2) Estimate of the difference with respect to placebo (95% CI) 36.4 (20.4, 52.5) 25.0 (9.2, 40.8) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. HAQ response is achieved if the reduction from baseline in HAQ score is at least All subjects who discontinued the study were considered HAQ non-responders at all subsequent time points. --- Figure 5: Proportion of Subjects with an HAQ Response (at least a 0.3 Reduction in HAQ Score) at Day 169 with 95 Percent Confidence Intervals 12

13 Health Outcomes (SF-36): Statistically significant improvements in Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF-36 were observed for the abatacept group compared with the placebo group at Days 169 (p < 0.001). Significant improvements in all physical health domains and mental health domains of the SF-36 were observed for the abatacept group compared with the placebo group at Days 169 (Figure. 6). Figure 6: Mean Treatment Difference (with 95 percent CI) in Change From Baseline of SF-36 Domains Between Groups (10 and 2 mg/kg) and Placebo on Day

14 Pharmacodynamics: The biomarkers evaluated were sensitive to active treatment with abatacept, showing generally dosedependent decrease in mean values for most of the parameters measured at Day 169 (Table. 7). Only TNFα did not show the same trend, but most of samples were under limit of detection (under 5.0 pg/ml). Table 7: Pharmacodynamic Measures at Day 169 Rheumatoid Factor (IU/mL) 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 n B/L Mean (SD) (254.7) (360.9) (324.3) Post B/L Mean (SD) (266.2) (473.3) (383.1) Change from B/L Mean (SE) (16.4) 6.4 (21.5) 26.9 (25.1) 95% CI -80.1, , , 77.2 sil-2r (IU/mL) n B/L Mean (SD) (492.6) (304.9) (252.6) Post B/L Mean (SD) (208.1) (282.2) (316.6) Change from B/L Mean (SE) (53.3) (32.9) 22.1 (27.3) 95% CI , , , 76.8 TNFα (pg/ml) n B/L Mean (SD) 5.3 (1.2) 8.0 (19.4) 7.7 (19.0) Post B/L Mean (SD) 5.0 (0.3) 5.7 (4.1) 6.5 (9.8) Change from B/L Mean (SE) -0.3 (0.2) -2.3 (1.9) -1.2 (1.2) 95% CI -0.6, , , 1.2 IL-6 (pg/ml) n B/L Mean (SD) 31.0 (25.4) 30.4 (32.3) 39.4 (42.2) Post B/L Mean (SD) 13.2 (20.2) 23.0 (35.9) 51.6 (89.5) Change from B/L Mean (SE) (3.3) -7.4 (5.5) 12.3 (10.3) 95% CI -24.2, , ,

15 Table 7: Pharmacodynamic Measures at Day 169 sicam-1 (ng/ml) 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 n B/L Mean (SD) (107.5) (123.8) (78.2) Post B/L Mean (SD) (84.4) (114.2) (71.8) Change from B/L Mean (SE) (8.6) (9.3) (7.6) 95% CI -76.0, , , -1.3 E-selectin (ng/ml) n B/L Mean (SD) 49.6 (30.4) 45.7 (28.3) 50.0 (27.9) Post B/L Mean (SD) 36.6 (22.3) 38.9 (19.2) 50.8 (31.4) Change from B/L Mean (SE) (2.4) -6.8 (1.9) 0.8 (1.9) 95% CI -17.8, , , 4.6 Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. Pharmacokinetics: The results of the phamacokinetics will be prepared and reported separately. 15

16 Safety: The AE profile was generally similar among the 3 treatment groups. given for 6 months was well tolerated and had a safety profile generally similar to that of placebo on background MTX. The overall rates of AEs were similar between the 2 active groups, and were slightly higher (10 mg/kg: 73.8 %; 2 mg/kg: 73.1 %) compared with the placebo group (63.6 %) (Table. 8). The majority of AEs reported with abatacept and placebo were mild to moderate in intensity. Few SAEs were reported in this study with overall rates similar between the abatacept groups and the placebo group (abatacept 10 mg/kg group: 8.2 % vs placebo group 9.1 %). Only two subjects discontinued due to AEs (Acute myocardial infarction and Vernet's syndrome) (Table. 8). No deaths and malignancies were reported (Table. 9). Infections and infestations (mainly Nasopharyngitis) were seen in a higher proportion of subjects in the abatacept groups (10 mg/kg: 32.8 %; 2 mg/kg: 41.8 %) than in the placebo group (24.2 %). Serious infections were only reported by one subject in the 10 mg/kg group (Table. 10). Most of all infections and infestations were generally mild or moderate, treatable. Only a Parvovirus infection (and Aplasia pure red cell) in the 10 mg/kg group was severe. Event resolved No subjects discontinued due to infection The overall profile of peri-infusional AEs was similar between the abatacept groups and the placebo group. The overall frequency of peri-infusional AEs was higher in the abatacept 2 mg/kg group (10mg/kg: 16.4 %; 2 mg/kg: 25.4 %; placebo: 15.2 %). All peri-infusional AEs reported with abatacept and placebo were mild to moderate in intensity. No AEs were developed during intravenous administration of abatacept in the 10 mg/kg and placebo groups. Flushing and Feeling abnormal was reported in 2 (3.0%) subjects and 1 (1.5%) subject, respectively in the 2 mg/kg group. All of them were mild and recovered on the same day wtihout any treatment. No autoimmune symptoms and disorders were reported in the 10 mg/kg and placebo groups. Basedow's disease was only reported in 1 (1.5%) subjects in the 2 mg/kg group. The subject has Basedow's disease as complication, and this AE in CRF was Ingravescence of Basedow's disease. No major autoimmune diseases (e.g. lupus or demyelination) were reported during the study. No safety issues emerged from the evaluation of laboratory data. Only Alanine aminotransferase (ALT) increase was seen in a higher proportion of subjects in the abatacept groups (10 mg/kg: 11.5 %; 2 mg/kg: 9.0 %) than in the placebo group (1.5 %). The results of the immunogenicity will be prepared and reported separately. 16

17 Table 8: Summary of Subjects with Adverse Events 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 Deaths Subjects with SAEs 5 (8.2) 2 (3.0) 6 (9.1) Subjects who Discontinued due to SAEs (3.0) Subjects with Related SAEs 2 (3.3) 0 1 (1.5) Subjects who Discontinued due to AEs (3.0) Subjects with AEs 45 (73.8) 49 (73.1) 42 (63.6) Subjects with Related AEs 30 (49.2) 40 (59.7) 24 (36.4) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. Table 9: Summary of Subjects with Laborartory Adverse Events 10 mg/kg 2 mg/kg Placebo N=61 N=67 N=66 Deaths Subjects with Lab SAEs Subjects who Discontinued due to Lab SAEs Subjects with Related Lab SAEs Subjects who Discontinued due to Lab AEs Subjects with Lab AEs 19 (31.1) 25 (37.3) 19 (28.8) Subjects with Related Lab AEs 14 (23.0) 15 (22.4) 11 (16.7) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 17

18 Table 10: Number of Subjects with Adverse Events (At Least 3% of Subjects in Any Therapy Group) Approved v2.0 Number (%) of Subjects 10 mg/kg + MTX 2 mg/kg + MTX Placebo + MTX Preferred Term N=61 N=67 N=66 Total Subjects with AEs 45 (73.8) 49 (73.1) 42 (63.6) Nasopharyngitis 13 (21.3) 18 (26.9) 8 (12.1) Upper respiratory tract inflammation 5 (8.2) 3 (4.5) 3 (4.5) Stomatitis 5 (8.2) 2 (3.0) 3 (4.5) Blood pressure increased 2 (3.3) 5 (7.5) 1 (1.5) Headache 2 (3.3) 4 (6.0) 3 (4.5) Dizziness 2 (3.3) 3 (4.5) 2 (3.0) Diarrhoea 2 (3.3) 1 (1.5) 2 (3.0) Nausea 2 (3.3) 1 (1.5) 2 (3.0) Eczema 2 (3.3) 1 (1.5) 2 (3.0) Pharyngitis 2 (3.3) 1 (1.5) 1 (1.5) Rash 2 (3.3) 1 (1.5) 1 (1.5) Conjunctivitis 2 (3.3) 1 (1.5) 0 Spinal compression fracture 2 (3.3) 1 (1.5) 0 Weight decreased 2 (3.3) 0 1 (1.5) 18

19 Table 10: Number of Subjects with Adverse Events (At Least 3% of Subjects in Any Therapy Group) Approved v2.0 Number (%) of Subjects 10 mg/kg + MTX 2 mg/kg + MTX Placebo + MTX Preferred Term N=61 N=67 N=66 Dry eye 2 (3.3) 0 0 Cough 1 (1.6) 2 (3.0) 2 (3.0) Feeling abnormal 1 (1.6) 2 (3.0) 0 Constipation 1 (1.6) 1 (1.5) 4 (6.1) Pyrexia 1 (1.6) 1 (1.5) 4 (6.1) Abdominal pain upper 1 (1.6) 1 (1.5) 2 (3.0) Erythema 1 (1.6) 1 (1.5) 2 (3.0) Blood glucose decreased 1 (1.6) 0 2 (3.0) Pruritus 1 (1.6) 0 2 (3.0) Cystitis 0 4 (6.0) 0 Hypertension 0 3 (4.5) 1 (1.5) Glossitis 0 3 (4.5) 0 Tinea pedis 0 2 (3.0) 2 (3.0) Pharyngolaryngeal pain 0 2 (3.0) 2 (3.0) Pharyngeal erythema 0 2 (3.0) 1 (1.5) Flushing 0 2 (3.0) 0 19

20 Table 10: Number of Subjects with Adverse Events (At Least 3% of Subjects in Any Therapy Group) Approved v2.0 Number (%) of Subjects 10 mg/kg + MTX 2 mg/kg + MTX Placebo + MTX Preferred Term N=61 N=67 N=66 Insomnia 0 1 (1.5) 3 (4.5) Stomach discomfort 0 1 (1.5) 2 (3.0) Bronchitis 0 1 (1.5) 2 (3.0) Blood pressure decreased 0 1 (1.5) 2 (3.0) Wound (3.0) Rheumatoid arthritis (3.0) Ingrowing nail (3.0) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 20

21 Table 11: Number of Subjects with Laborartory Adverse Events(At Least 3% of Subjects in Any Therapy Group) Approved v2.0 Number (%) of Subjects 10 mg/kg + MTX 2 mg/kg + MTX Placebo + MTX Preferred Term N=61 N=67 N=66 Total Subjects with AEs 19 (31.1) 25 (37.3) 19 (28.8) Alanine aminotransferase increased 7 (11.5) 6 (9.0) 1 (1.5) White blood cell count increased 5 (8.2) 10 (14.9) 6 (9.1) Aspartate aminotransferase increased 4 (6.6) 3 (4.5) 1 (1.5) Blood glucose increased 3 (4.9) 4 (6.0) 5 (7.6) Lymphocyte count decreased 2 (3.3) 4 (6.0) 7 (10.6) White blood cells urine positive (3.0) Glucose urine present 0 2 (3.0) 2 (3.0) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 21

22 Table 12: Number of Subjects with Serious Adverse Events Number (%) of Subjects System Organ Class 10 mg/kg 2 mg/kg Placebo Approved v2.0 Preferred Term N=61 N=67 N=66 Total Subjects with AEs 5 (8.2) 2 (3.0) 6 (9.1) Blood and lymphatic system disorders 1 (1.6) 0 0 Aplasia pure red cell 1 (1.6) 0 0 Cardiac disorders (1.5) Acute myocardial infarction (1.5) Gastrointestinal disorders 1 (1.6) 0 0 Abdominal pain 1 (1.6) 0 0 Vomiting 1 (1.6) 0 0 Hepatobiliary disorders 0 1 (1.5) 0 Cholelithiasis 0 1 (1.5) 0 Infections and infestations 1 (1.6) 0 0 Parvovirus infection 1 (1.6) 0 0 Injury, poisoning and procedural complications 2 (3.3) 0 1 (1.5) Spinal compression fracture 2 (3.3) 0 0 Fibula fracture (1.5) Tibia fracture (1.5) 22

23 Table 12: Number of Subjects with Serious Adverse Events Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Musculoskeletal and connective tissue disorders 1 (1.6) 0 2 (3.0) Rheumatoid arthritis (3.0) Arthritis 1 (1.6) 0 0 Nervous system disorders (3.0) Dizziness (1.5) Vernet's syndrome (1.5) Renal and urinary disorders 0 1 (1.5) 0 Calculus ureteric 0 1 (1.5) 0 Respiratory, thoracic and mediastinal disorders 1 (1.6) 0 0 Upper respiratory tract inflammation 1 (1.6) 0 0 Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 23

24 Table 13: Number of Subjects with Peri-Infusional Adverse Events Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Total Subjects with AEs 10 (16.4) 17 (25.4) 10 (15.2) Cardiac disorders 1 (1.6) 0 0 Palpitations 1 (1.6) 0 0 Eye disorders 0 1 (1.5) 0 Asthenopia 0 1 (1.5) 0 Conjunctivitis allergic 0 1 (1.5) 0 Gastrointestinal disorders 3 (4.9) 3 (4.5) 1 (1.5) Diarrhoea 1 (1.6) 1 (1.5) 1 (1.5) Aphthous stomatitis 1 (1.6) 1 (1.5) 0 Cheilitis 1 (1.6) 0 0 Periodontitis 0 1 (1.5) 0 General disorders and administration site conditions 2 (3.3) 3 (4.5) 2 (3.0) Feeling abnormal 0 2 (3.0) 0 Pyrexia 1 (1.6) 0 1 (1.5) Asthenia 0 1 (1.5) 0 Injection site rash (1.5) Venipuncture site swelling 1 (1.6)

25 Table 13: Number of Subjects with Peri-Infusional Adverse Events Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Infections and infestations 2 (3.3) 3 (4.5) 1 (1.5) Nasopharyngitis 1 (1.6) 2 (3.0) 1 (1.5) Cystitis 0 1 (1.5) 0 Pharyngitis 1 (1.6) 0 0 Investigations 2 (3.3) 6 (9.0) 4 (6.1) Blood pressure increased 1 (1.6) 4 (6.0) 1 (1.5) Blood pressure decreased 0 1 (1.5) 2 (3.0) Blood pressure diastolic decreased 1 (1.6) 0 0 Blood pressure systolic decreased 0 1 (1.5) 0 Blood pressure systolic increased (1.5) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 (1.5) 0 Seborrhoeic keratosis 0 1 (1.5) 0 Nervous system disorders 1 (1.6) 4 (6.0) 2 (3.0) Headache 1 (1.6) 2 (3.0) 2 (3.0) Dizziness 0 1 (1.5) 0 Dysgeusia 0 1 (1.5) 0 25

26 Table 13: Number of Subjects with Peri-Infusional Adverse Events Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Psychiatric disorders 1 (1.6) 0 0 Anxiety disorder 1 (1.6) 0 0 Renal and urinary disorders 0 1 (1.5) 0 Urinary incontinence 0 1 (1.5) 0 Respiratory, thoracic and mediastinal disorders 0 1 (1.5) 0 Pharyngolaryngeal pain 0 1 (1.5) 0 Skin and subcutaneous tissue disorders 2 (3.3) 0 1 (1.5) Eczema 1 (1.6) 0 0 Pruritus 1 (1.6) 0 0 Rash (1.5) Vascular disorders 1 (1.6) 3 (4.5) 0 Flushing 0 2 (3.0) 0 Hypertension 0 1 (1.5) 0 Hot flush 1 (1.6) 0 0 Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 26

27 Table 14: Infections (Adverse Events Within System Organ Class: Infections and Infestations) Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Infections and infestations 20 (32.8) 28 (41.8) 16 (24.2) Nasopharyngitis 13 (21.3) 18 (26.9) 8 (12.1) Pharyngitis 2 (3.3) 1 (1.5) 1 (1.5) Sinusitis 1 (1.6) 1 (1.5) 0 Gastroenteritis 1 (1.6) 0 0 Keratitis herpetic 1 (1.6) 0 0 Localised infection 1 (1.6) 0 0 Nail tinea 1 (1.6) 0 0 Parvovirus infection 1 (1.6) 0 0 Cystitis 0 4 (6.0) 0 Tinea pedis 0 2 (3.0) 2 (3.0) Bronchitis 0 1 (1.5) 2 (3.0) Cellulitis 0 1 (1.5) 0 Gastroenteritis viral 0 1 (1.5) 0 Hordeolum 0 1 (1.5) 0 Pneumonia 0 1 (1.5) 0 Rash pustular 0 1 (1.5) 0 Upper respiratory tract infection 0 1 (1.5) 0 Skin candida 0 1 (1.5) 0 Tinea faciei 0 1 (1.5) 0 27

28 Table 14: Infections (Adverse Events Within System Organ Class: Infections and Infestations) Approved v2.0 System Organ Class 10 mg/kg Number (%) of Subjects 2 mg/kg Placebo Preferred Term N=61 N=67 N=66 Herpes zoster (1.5) Oral candidiasis (1.5) Otitis media (1.5) Periodontal infection (1.5) Pulpitis dental (1.5) Tonsillitis (1.5) Source: Statistical analysis result for clinical study (Reported: 17 Mar 2008) Data set: All treated subjects. 28

29 PRELIMINARY ASSESSMENT: 2 or 10 mg/kg or placebo combined with MTX showed a dose response based on ACR 20 at Day 169. ACR20 in 10 mg/kg was statistically significant higher than that of placebo, and was numercially higher than that of 2mg/kg. Overall, the 10 mg/kg dose performed numnerically better than the 2 mg/kg as shown by the ACR50, 70 and the HAQ response Overall response was somewhat higher than previous foreign study IM101100, however, the foreign study used a higher MTX dose. Both of this study and foreign IM study, study population was the subjects with active rheumatoid arthritis defined as 10 or more swollen joints, 12 or more tender joint counts and CRP level 1 mg/dl, and an inadequate clinical response to methotrexate while receiving methotrexate. However, MTX dose of (defined within 6-8 mg/week; Mean MTX dose 7 mg/week) was lower than those of IM (defined within mg weekly; Mean MTX dose 15 mg/week) NOTE: The mean weights in kg of and IM were 55 kg and 80 kg, respectively. Safety of the 10 mg/kg indicated that the molecule had a favorable benefit risk profile in Japanese subjects, similar to the foreign studies. Safety of 10mg/kg and 2mg/kg were similar. 29