The Effects of Golimumab on Radiographic Progression in Rheumatoid Arthritis

ARTHRITIS & RHEUMATISM Vol. 63, No. 5, May 2011, pp 1200 1210 DOI 10.1002/art.30263 2011, American College of Rheumatology The Effects of Golimumab on Radiographic Progression in Rheumatoid Arthritis Results of Randomized Controlled Studies of Golimumab Before Methotrexate Therapy and Golimumab After Methotrexate Therapy Paul Emery, 1 Roy Fleischmann, 2 Désirée van der Heijde, 3 Edward C. Keystone, 4 Mark C. Genovese, 5 Philip G. Conaghan, 1 Elizabeth C. Hsia, 6 Weichun Xu, 7 Anna Baratelle, 8 Anna Beutler, 7 and Mahboob U. Rahman 9 Objective. To evaluate the effects of golimumab on radiographic progression in patients with rheumatoid arthritis (RA). Methods. Methotrexate (MTX) naive patients (in the Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [GO-BEFORE] study; n 637) and patients with active RA despite MTX therapy (in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [GO-FORWARD] study; n Supported by Centocor Research and Development, Inc. (a subsidiary of Johnson & Johnson) and Schering-Plough/Merck Research Institute. 1 Paul Emery, MA, MD, FRCP, Philip G. Conaghan, MB BS, PhD, FRACP, FRCP: University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK; 2 Roy Fleischmann, MD: University of Texas Southwest Medical Center at Dallas; 3 Désirée van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 4 Edward C. Keystone, MD, FRCP: University of Toronto and Mount Sinai Hospital, Toronto, Ontario, Canada; 5 Mark C. Genovese, MD: Stanford University, Palo Alto, California; 6 Elizabeth C. Hsia, MD: Centocor Research and Development, Inc., Malvern, Pennsylvania, and University of Pennsylvania School of Medicine, Philadelphia; 7 Weichun Xu, PhD, Anna Beutler, MD: Centocor Research and Development, Inc., Malvern, Pennsylvania; 8 Anna Baratelle, ASRT: Baratelle and Associates, LLC, Springfield, Pennsylvania; 9 Mahboob U. Rahman, MD, PhD: Pfizer, Collegeville, Pennsylvania. Dr. Emery has received consulting fees, speaking fees, and/or honoraria from MSD, Pfizer, Roche, Bristol-Myers Squibb, and Abbott (less than $10,000 each). Dr. Fleischmann has received consulting fees, speaking fees, and/or honoraria from Centocor (less than $10,000). Dr. van der Heijde has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, AstraZeneca, Bristol- Myers Squibb, Centocor, Chugai, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough/ Merck, UCB, and Wyeth (less than $10,000 each). Dr. Keystone has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Bristol-Myers Squibb, Centocor, F. Hoffmann-La Roche, Genentech, Schering-Plough/Merck, UCB, and Pfizer (less than 444) were randomly assigned to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab or placebo was administered subcutaneously every 4 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO- FORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score. Results. In the GO-BEFORE study, the mean SD changes in the modified Sharp score from baseline to week 52 (control period) were 1.4 4.6 in group 1, 1.3 6.2 in group 2 (P 0.266), 0.7 5.2 in group 3 (P 0.015), and 0.1 1.8 in group 4 (P 0.025). In the GO-FORWARD study, changes from baseline to week 24 (control period) were 0.6 2.4 in group 1, 0.3 1.6 in group 2 (P 0.361), 0.6 2.7 in group 3 (P 0.953), and 0.2 1.3 in group 4 (P 0.293). $10,000 each) and has received research funding from Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, F. Hoffmann-La Roche, Novartis, Schering-Plough/Merck, UCB, and Wyeth. Dr. Genovese has received grant support from, and served as a consultant to, Johnson & Johnson. Dr. Conaghan has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Roche, Novartis, MSD, and Bristol-Myers Squibb (less than $10,000 each). Drs. Hsia, Xu, Beutler, and Rahman own stock or stock options in Johnson & Johnson. Address correspondence to Paul Emery, MA, MD, FRCP, Academic Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. E-mail: p.emery@leeds.ac.uk. Submitted for publication April 16, 2010; accepted in revised form January 18, 2011. 1200

EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA 1201 Conclusion. Golimumab in combination with MTX inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study. Radiographic progression in the GO-FORWARD study was minimal in all treatment arms, precluding an adequate assessment of the effect of golimumab on radiographic progression in this study. Golimumab is a human monoclonal antibody to tumor necrosis factor (TNF ). The effect of golimumab in rheumatoid arthritis (RA) was evaluated in 3 large, phase III clinical studies that included populations of patients with different exposures to previous therapies (1 3). The Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset (GO-BEFORE) study included patients with active RA who were naive to methotrexate (MTX), the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy (GO- FORWARD) study included patients with active RA despite MTX therapy, and the Golimumab in Patients with Active Rheumatoid Arthritis After Treatment with Tumour Necrosis Factor Inhibitors (GO-AFTER) study included patients with active RA who had previously received anti-tnf therapy. The primary efficacy end points were related to signs and symptoms and the safety results for these studies have been previously reported (1 3). Radiographic progression, however, was a coprimary end point in the GO-BEFORE study and a secondary end point in the GO-FORWARD study; the GO-AFTER study did not include radiographic evaluations. The objective of the current analysis was to therefore evaluate the effect of golimumab on radiographic progression in patients with RA who participated in the GO-BEFORE and GO-FORWARD trials. PATIENTS AND METHODS The study design and patient inclusion criteria of the GO-BEFORE (1) and GO-FORWARD (2) studies have been published previously. The GO-BEFORE population consisted of 637 patients with RA who were MTX naive (defined as having taken no more than 3 weekly doses of MTX for RA at any time), while the GO-FORWARD population consisted of 444 patients who had active RA despite having taken MTX. These patients were to have tolerated MTX at a dosage of 15 mg/week for at least 3 months before screening, with receipt of a stable dosage of 15 25 mg/week during the 4-week period immediately preceding screening (2). In both studies, active RA was defined as the presence of 4 swollen joints (of 66 total joints assessed), 4 tender joints (of 68 total joints assessed), and at least 2 of the following 4 features: a C-reactive protein (CRP) level of 1.5 mg/dl (normal 0 0.6) or an erythrocyte sedimentation rate (Westergren) of 28 mm/hour; morning stiffness of at least 30 minutes duration; presence of bone erosion, as determined by radiograph and/or magnetic resonance imaging; or presence of anti cyclic citrullinated peptide antibody or rheumatoid factor (1,2). In both studies, patients were randomly assigned to receive placebo injections plus MTX capsules (group 1), golimumab 100-mg injections plus placebo capsules (group 2), golimumab 50-mg injections plus MTX capsules (group 3), or golimumab 100-mg injections plus MTX capsules (group 4). Golimumab and placebo injections were administered subcutaneously every 4 weeks. In the GO-BEFORE study, group 1 was an active comparator group because all patients were MTX naive. In the GO-FORWARD study, all patients had had an inadequate response to MTX therapy, so group 1 served as a placebo comparator. Randomization in the GO- BEFORE study was stratified according to the CRP level at screening ( 1.5 mg/dl or 1.5 mg/dl); randomization was not stratified by the CRP level in the GO-FORWARD study. Both studies were conducted according to the principles of the Declaration of Helsinki, and all patients provided written informed consent before participating in the study. At week 28 in the GO-BEFORE study and at week 16 in the GO-FORWARD study, patients with 20% improvement in both the tender joint count and the swollen joint count entered a double-blind early escape phase, during which those in group 1 received golimumab 50 mg plus MTX, those in group 2 received golimumab 100 mg plus MTX, and those in group 3 received golimumab 100 mg plus MTX (Figure 1). Patients in group 4 who met the criteria for early escape did not receive study medication adjustments. In the GO- FORWARD study, patients in group 1 who did not enter the early escape phase crossed over to golimumab 50 mg plus MTX at week 24. Thus, the duration of the placebocomparator portion of the GO-FORWARD study was 24 weeks. The duration of the active-comparator portion of the GO-BEFORE study was 52 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO-FORWARD study (Figure 1). Baseline radiographs were taken within 4 weeks prior to the first dose. Patients who discontinued injections had radiographs taken at the time of discontinuation unless radiographs had been obtained within the previous 8 weeks. In the GO- FORWARD study, patients in group 4 who met the criteria for early escape did not receive medication adjustments, but radiographs were taken at week 16 for consistency with patients in the other groups, thus maintaining the blind. Radiographs were scored by 2 independent readers (different pairs of readers for the GO-BEFORE and the GO-FORWARD studies) and an adjudicator, using the Sharp score as modified by van der Heijde (4). Readers were blinded to the patient s identity, the treatment group assignment, and the time point at which the radiograph was taken. Ten percent of images were randomly selected and scored a second time in a blinded manner so that intrareader variability could be determined.

1202 EMERY ET AL Figure 1. Study diagram for A, the Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset (GO-BEFORE) study and B, the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy (GO-FORWARD) study. Numbers in parentheses are the number of patients with evaluable radiographs at each time point. Radiographs were obtained at baseline, week 24 or 28, and week 52. In the GO-FORWARD study, patients who entered the double-blind early-escape phase underwent radiography at week 16. In both studies, for patients who met the criteria for early escape, the radiographic scores for subsequent time points were linearly extrapolated. Intention-to-treat principles were used in the data analyses. Images that were taken more than 8 weeks before or after a scheduled visit date or were not taken at all were considered to be missing. For patients who had missing modified Sharp scores at the study end point but had scores at 2 points before that end point, linear extrapolation was used to impute the end point score. For patients who met the criteria for early escape in the GO-BEFORE study, the week 52 radiographic scores were imputed using linear extrapolation from the baseline and week 28 scores. For patients who met the criteria for early escape in the GO-FORWARD study, the week 24 and week 52 scores were imputed using linear extrapolation from the baseline and week 16 scores. For patients in group 1 of the GO-FORWARD study who crossed over from placebo plus MTX to golimumab 50 mg plus MTX at week 24, the week 52 scores were imputed using linear extrapolation from the baseline and week 24 scores. In the GO-BEFORE study, the change in the modified Sharp score from baseline to week 52 was a co-primary end point. Results for the study s other co-primary end point, the percentage of patients achieving at least 50% improvement according to the American College of Rheumatology criteria (ACR50) (5) at week 24, have been reported previously (1). In the GO-FORWARD study, radiographic outcomes were secondary end points. Analysis of variance on the van der Waerden normal scores (a test for data that are not normally distributed) (6) was used to evaluate differences between golimumab and control groups for continuous variables, while Cochran-Mantel-Haenszel methodology was used for categorical variables. We also evaluated the proportion of patients with a change in the modified Sharp score of 0 and with a change in the modified Sharp score that was greater than the smallest detectable change (SDC) (7). In both studies, Type I error at the 0.05 level of significance was preserved with a hierarchical approach to control for multiplicity when testing each of the efficacy end points, wherein the comparison between combined groups 3 and 4 versus group 1 was made first. If there was a significant difference between combined groups 3 and 4 versus group 1, pairwise comparisons between group 3 and group 1 and between group 4 and group 1 were performed. Then, if a statistically significant difference was found for at least 1 of these pairwise comparisons, group 2 and group 1 were compared. The co-primary end points for the GO-BEFORE study were considered to have been met if the differences between combined groups 3 and 4, as well as the differences between at least one of group 3 or group 4 versus group 1, were statistically significant. This same approach was applied to the GO-

EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA 1203 Table 1. Baseline clinical characteristics of rheumatoid arthritis patients in the GO-BEFORE and GO-FORWARD studies* Characteristic Group 1, placebo plus MTX Group 2, golimumab 100 mg plus placebo Group 3, golimumab 50 mg Golimumab plus MTX Group 4, golimumab 100 mg GO-BEFORE study No. of patients randomized to treatment 160 159 159 159 No. (%) female 134 (83.8) 134 (84.3) 135 (84.9) 125 (78.6) Age, years 50 (40, 57) 49 (39, 56) 51 (45, 58) 50 (41, 58) Disease duration, years 1.2 (0.5, 3.2) 1.8 (0.6, 4.7) 1.0 (0.5, 3.3) 1.3 (0.5, 4.3) No. of swollen joints (66 assessed) 11 (7, 19) 12 (7, 19) 13 (9, 21) 14 (8, 20) No. of tender joints (68 assessed) 26 (14, 38) 25 (15, 37) 26 (15, 40) 26 (15, 35) HAQ DI score (range 0 3) 1.5 (1.1, 1.9) 1.8 (1.0, 2.1) 1.5 (1.1, 2.0) 1.6 (1.0, 2.0) CRP, mg/dl 1.4 (0.6, 3.3) 1.3 (0.5, 3.5) 1.3 (0.5, 3.1) 1.3 (0.3, 3.4) ESR, mm/hour 37.5 (26.0, 65.0) 40.0 (26.0, 60.0) 40.0 (29.0, 60.0) 36.0 (25.0, 60.0) DAS28-ESR score 6.1 (5.3, 7.1) 6.4 (5.6, 7.3) 6.3 (5.7, 7.0) 6.3 (5.5, 7.1) No. (%) RF positive 130 (81.8) 129 (81.1) 121 (76.1) 127 (79.9) No. (%) anti-ccp antibody positive 121 (75.6) 125 (78.6) 106 (66.7) 116 (73.0) No. (%) taking corticosteroids 83 (51.9) 86 (54.8) 82 (51.6) 80 (50.3) Prednisone equivalent dosage, mg/day 5.0 (5.0, 7.5) 5.0 (5.0, 10.0) 5.0 (5.0, 10.0) 5.5 (5.0, 10.0) No. (%) with modified Sharp score 0 153 (95.6) 153 (96.2) 154 (96.9) 152 (95.6) GO-FORWARD study No. of patients randomized to treatment 133 133 89 89 No. (%) female 109 (82.0) 105 (78.9) 72 (80.9) 72 (80.9) Age, years 52 (42, 58) 51 (42, 59) 52 (43, 57) 50 (45, 56) Disease duration, years 6.5 (3.1, 11.9) 5.9 (2.4, 12.2) 4.5 (2.1, 9.7) 6.7 (2.4, 14.3) No. of swollen joints (66 assessed) 12 (8, 19) 11 (8, 17) 13 (8, 22) 12 (8, 18) No. of tender joints (68 assessed) 21 (14, 34) 22 (14, 32) 26 (16, 39) 23 (15, 33) HAQ DI score (range 0 3) 1.3 (0.8, 1.8) 1.4 (0.9, 1.9) 1.4 (1.0, 1.9) 1.4 (0.9, 1.9) CRP, mg/dl 0.8 (0.3, 2.0) 0.9 (0.4, 2.5) 1.0 (0.4, 2.8) 0.9 (0.4, 2.4) ESR, mm/hour 34.0 (18.0, 48.0) 36.0 (22.0, 50.0) 37.0 (23.0, 55.0) 34.0 (22.0, 48.0) DAS28-ESR score 6.1 (5.3, 6.6) 6.0 (5.2, 6.8) 6.1 (5.4, 6.9) 5.9 (5.3, 6.8) No. (%) RF positive 108 (81.2) 111 (83.5) 77 (86.5) 75 (84.3) No. (%) anti-ccp antibody positive 107 (80.5) 106 (79.7) 72 (80.9) 68 (76.4) No. (%) taking corticosteroids 87 (65.4) 90 (67.7) 67 (75.3) 62 (69.7) Prednisone equivalent dosage, mg/day 7.3 (5.0, 10.0) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0) No. (%) with modified Sharp score 0 118 (88.7) 122 (91.7) 81 (91.0) 77 (86.5) * Except where indicated otherwise, values are the median (interquartile range). GO-BEFORE Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset; GO-FORWARD Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy; MTX methotrexate; HAQ Health Assessment Questionnaire; DI disability index; CRP C-reactive protein; ESR erythrocyte sedimentation rate; DAS28-ESR Disease Activity Score 28-joint assessment (3-variable) using the ESR; RF rheumatoid factor; anti-ccp anti cyclic citrullinated peptide. Of 159 patients tested. Of 157 patients tested. FORWARD analyses; however, assessments of structural damage were secondary end points for the GO-FORWARD study. All analyses were prespecified in the statistical analysis plan. Power calculations for the ACR50 co-primary end point in the GO-BEFORE study were reported previously (1). For the modified Sharp score co-primary end point, based on 10,000 simulations, the sample size of 150 patients per treatment group was expected to provide 90% power to detect a difference in the change from baseline at week 52 in the modified Sharp score between the combined groups 3 and 4 versus group 1, using a 2-sided t-test on the van der Waerden normal scores at the level of 0.05, assuming the mean change from baseline in modified Sharp score was 3.5 for group 1 and 0.5 1.5 for combined groups 3 and 4. Simulations were performed using standard deviations ranging from 0.6 to 0.9. Power calculations for the signs and symptoms end points in the GO-FORWARD study were reported previously (2). Radiographic end points were not considered in the power calculations in the GO-FORWARD study. RESULTS Baseline demographic and disease characteristics were well balanced among the treatment groups in each study (Table 1). As expected, patients in the GO- BEFORE study had a shorter median disease duration than those in the GO-FORWARD study, but had slightly more active disease and greater physical disability, as indicated by the median CRP levels, the Disease

1204 EMERY ET AL Table 2. Summary of modified Sharp scores at baseline and changes from baseline to week 24 or 28 and from baseline to week 52 in the GO-BEFORE and GO-FORWARD studies* Characteristic Group 1, placebo plus MTX Group 2, golimumab 100 mg plus placebo Group 3, golimumab 50 mg Golimumab plus MTX Group 4, golimumab 100 mg Groups 3 and 4 combined GO-BEFORE study No. of patients randomized 160 159 159 159 318 Baseline score Mean SD 19.7 35.4 20.4 30.9 18.7 32.4 18.2 35.5 18.5 33.9 Median (IQR) 5.25 (2.00, 18.1) 6.00 (2.50, 26.5) 5.50 (2.00, 19.5) 6.00 (2.50, 18.0) 6.00 (2.00, 18.0) Estimated yearly rate of progression 12.7 12.1 13.7 10.3 12.0 Change from baseline to week 28 Mean SD 1.11 3.88 0.61 3.55 0.71 3.77 0.01 1.47 0.36 2.89 Median (IQR) 0.00 (0.00, 1.00) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) P 0.054 0.065 0.003 0.005 Change from baseline to week 52 Mean SD 1.37 4.56 1.25 6.16 0.74 5.23 0.07 1.83 0.41 3.93 Median (IQR) 0.00 (0.00, 1.50) 0.00 (0.00, 1.00) 0.00 ( 0.50, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) P 0.266 0.015 0.025 0.006 CRP 1.5 mg/dl at screening No. of patients 83 80 82 82 164 Mean SD 0.98 3.990 0.02 2.04 0.07 1.34 0.10 1.17 0.08 1.25 Median (IQR) 0.00 (0.00, 0.50) 0.00 ( 0.50, 0.25) 0.00 ( 0.50, 0.00) 0.00 (0.00, 0.50) 0.00 ( 0.25, 0.25) CRP 1.5 mg/dl at screening No. of patients 77 79 77 77 154 Mean SD 1.80 5.16 2.50 8.33 1.47 7.35 0.04 2.35 0.75 5.49 Median (IQR) 0.50 (0.00, 2.00) 0.00 (0.00, 1.81) 0.00 (0.00, 0.91) 0.00 (0.00, 0.50) 0.00 (0.00, 0.70) Change from baseline to week 52 76/141 (53.9) 82/137 (59.9) 100/140 (71.4) 85/139 (61.2) 185/279 (66.3) 0, no./no. evaluated (%) P 0.456 0.003 0.236 0.015 Change from baseline to week 52 17/141 (12.1) 12/137 (8.8) 9/140 (6.4) 3/139 (2.2) 12/279 (4.3) SDC, no./no. evaluated (%) P 0.475 0.120 0.001 0.004 GO-FORWARD study No. of patients randomized 133 133 89 89 178 Baseline score Mean SD 36.7 52.1 37.4 52.5 29.7 39.3 39.6 56.1 34.6 48.5 Median (IQR) 17.5 (1.5, 49.5) 15.3 (2.5, 49.0) 9.5 (2.0, 49.6) 17.0 (3.0, 47.0) 14.0 (2.5, 49.3) Estimated yearly rate of progression 5.0 5.2 5.3 6.0 5.6 Change from baseline to week 24 Mean SD 0.55 2.35 0.27 1.60 0.60 2.74 0.23 1.34 0.41 2.16 Median (IQR) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) P 0.361 0.953 0.293 0.551 CRP 1.5 mg/dl at screening No. of patients 88 82 56 52 108 Mean SD 0.39 2.36 0.29 1.74 0.11 1.12 0.35 1.51 0.23 1.32 Median (IQR) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) CRP 1.5 mg/dl at screening No. of patients 45 51 33 37 70 Mean SD 0.85 2.34 0.24 1.37 1.44 4.17 0.05 1.07 0.70 3.02 Median (IQR) 0.00 (0.00, 1.00) 0.00 (0.00, 1.00) 0.00 (0.00, 1.50) 0.00 ( 0.50, 0.43) 0.00 (0.00, 0.90) Change from baseline to week 52 Mean SD 1.10 4.68 0.89 3.37 0.93 4.86 0.15 1.64 0.54 3.64 Median (IQR) 0.00 (0.00, 1.10) 0.00 (0.00, 1.00) 0.00 (0.00, 0.50) 0.00 (0.00, 0.85) 0.00 (0.00, 0.50) P 0.967 0.855 0.221 0.390 Change from baseline to week 24 81/122 (66.4) 85/124 (68.5) 57/86 (66.3) 58/84 (69.0) 115/170 (67.6) 0, no./no. evaluated P 0.718 0.986 0.689 0.822 Change from baseline to week 24 5/122 (4.1) 5/124 (4.0) 5/86 (5.8) 3/84 (3.6) 8/170 (4.7) SDC, no./no. evaluated P 0.979 0.569 0.847 0.804 * In the GO-BEFORE study, patients in group 1 who did not enter the double-blind early escape phase continued to receive placebo plus MTX through week 52. In the GO-FORWARD study, all patients in group 1 who did not enter the early escape phase crossed over to golimumab 50 mg plus MTX at week 24. Therefore, there is no placebo comparator after week 24 in the GO-FORWARD study. All P values are versus group 1. IQR interquartile range; SDC smallest detectable change. See Table 1 for other definitions. Mean of the modified Sharp score at baseline divided by the disease duration per patient. Change in the modified Sharp score from baseline to week 52 was a co-primary end point of the GO-BEFORE study, along with the proportion of patients who met the American College of Rheumatology 50% improvement criteria at week 24, the results of which were previously reported (1). All other radiographic outcomes were secondary end points in each study.

EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA 1205 Table 3. Erosion and joint space narrowing scores at baseline and changes from baseline to week 24 or 28 and from baseline to week 52 in the GO-BEFORE and GO-FORWARD studies* Characteristic Group 1, placebo plus MTX Group 2, golimumab 100 mg plus placebo Group 3, golimumab 50 mg Golimumab plus MTX Group 4, golimumab 100 mg Groups 3 and 4 combined GO-BEFORE study Erosion score Baseline Mean SD 11.3 18.6 11.7 16.3 10.8 17.4 10.5 19.4 10.6 18.4 Median (IQR) 4.00 (1.50, 12.1) 4.50 (2.00, 16.5) 4.50 (1.50, 11.5) 4.50 (1.50, 12.0) 4.50 (1.50, 11.5) Change from baseline to week 28 Mean SD 0.77 2.56 0.55 3.08 0.46 2.12 0.02 1.20 0.22 1.73 Median (IQR) 0.00 (0.00, 1.00) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 ( 0.50, 0.50) 0.00 (0.00, 0.50) Change from baseline to week 52 Mean SD 0.74 2.82 0.76 3.88 0.48 2.08 0.09 1.39 0.28 1.78 Median (IQR) 0.00 (0.00, 0.50) 0.00 ( 0.02, 0.50) 0.00 (0.00, 0.50) 0.00 ( 0.50, 0.50) 0.00 (0.00, 0.50) Joint space narrowing score Baseline Mean SD 8.37 17.8 8.70 15.7 7.89 16.1 7.75 17.2 7.82 16.7 Median (IQR) 1.00 (0.00, 6.75) 1.00 (0.00, 10.50) 1.50 (0.00, 6.50) 1.00 (0.00, 6.50) 1.00 (0.00, 6.50) Change from baseline to week 28 Mean SD 0.43 2.17 0.13 1.34 0.27 2.10 0.03 0.68 0.15 1.56 Median (IQR) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) Change from baseline to week 52 Mean SD 0.58 2.26 0.35 1.65 0.23 1.99 0.04 0.88 0.13 1.54 Median (IQR) 0.00 (0.00, 0.00) 0.00 (0.00, 0.50) 0.0 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) GO-FORWARD study Erosion score Baseline Mean SD 18.7 27.1 19.1 27.2 16.2 22.2 19.7 29.7 17.9 26.2 Median (IQR) 5.50 (1.00, 25.0) 8.00 (1.50, 25.0) 5.75 (1.50, 22.3) 7.00 (2.23, 23.5) 6.00 (2.00, 22.5) Change from baseline to week 24 Mean SD 0.19 0.75 0.01 0.86 0.26 1.63 0.09 0.96 0.18 1.34 Median (IQR) 0.00 (0.00, 0.50) 0.00 (0.00, 0.23) 0.00 (0.00, 0.50) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) Change from baseline to week 52 Mean SD 0.17 0.77 0.23 1.41 0.29 1.62 0.14 1.41 0.04 1.09 Median (IQR) 0.00 (0.00, 0.50) 0.00 ( 0.23, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.50) 0.00 (0.00, 0.00) Joint space narrowing score Baseline Mean SD 18.0 25.9 18.4 27.1 13.5 18.5 19.9 27.8 16.7 23.7 Median (IQR) 4.50 (0.00, 26.0) 6.50 (0.00, 25.0) 4.00 (0.00, 23.8) 9.00 (0.00, 26.0) 5.00 (0.00, 25.5) Change from baseline to week 24 Mean SD 0.32 1.75 0.23 1.20 0.23 0.85 0.15 0.90 0.19 0.87 Median (IQR) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) Change from baseline to week 52 Mean SD 0.36 2.34 0.64 2.50 0.22 0.92 0.23 0.94 0.24 0.97 Median (IQR) 0.00 (0.00, 0.00) 0.00 (0.00, 0.50) 0.00 (0.00, 0.23) 0.00 (0.00, 0.00) 0.00 (0.00, 0.00) * IQR interquartile range. See Table 1 for other definitions. Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) (8), and the median scores on the disability index (DI) of the Health Assessment Questionnaire (HAQ) (9). Also, at baseline, 96 97% of patients in the GO-BEFORE study and 87 92% of those in the GO-FORWARD study had a modified Sharp score 0. In the GO-BEFORE study, intraclass correlation estimates between the readers were 0.90 for baseline values and 0.90 for week 52 values. In the GO- FORWARD study, the intraclass correlation estimates were 0.95 for both baseline and week 24. The SDC in the total modified Sharp score was 2.7 in the GO-BEFORE study and 1.8 in the GO-FORWARD study. Radiographic scores at baseline and changes from baseline to week 24/28 and to week 52 are summarized in Table 2. Baseline radiographic scores were similar among the treatment groups in the GO- BEFORE study. However, in the GO-FORWARD study, patients in group 3 had lower modified Sharp scores than those in the other groups. At baseline, the median modified Sharp scores were greater in the GO-FORWARD study than in the GO-BEFORE study, which was expected for a patient population with a

1206 EMERY ET AL Figure 2. Changes in the modified Sharp scores from baseline to week 24 or 28 and to week 52 in A, the GO-BEFORE study and B, the GO-FORWARD study. Shown are the mean (solid horizontal line), median (dotted horizontal line), and interquartile range (IQR) (shaded bars) of the changes in radiographic scores from baseline in each treatment group. GLM golimumab. See Figure 1 for other definitions. longer disease duration. Baseline erosion and joint space narrowing scores are summarized in Table 3. The co-primary end point in the GO-BEFORE study was met. Patients in groups 3 and 4 had significantly less radiographic progression than patients in group 1 over the 52 weeks, during which there was a comparator group (Figure 2A and Table 2). No differences in the scores for patients in groups 1 and 2 were observed. Statistically significant differences between the combined groups 3 and 4 and group 1 and between group 4 and group 1 were also observed at week 28 (Table 2). There was a trend toward statistical significance for the difference between group 3 and group 1 at week 28 (P 0.065). The individual radiographic scores for each patient are given in the probability plot shown in Figure 3A. A significantly greater percentage of patients in combined groups 3 and 4 and in group 3 alone did not have an increase in the modified Sharp score (i.e., change from baseline to week 52 was 0) as compared with the patients in group 1; the difference between these percentages in groups 1 and 4 was not statistically significant (Table 2). In contrast, the percentage of patients with a change in the modified Sharp score greater than the SDC from baseline to week 52 was significantly higher in combined groups 3 and 4 and in group 4 alone as compared with group 1; the difference between group 3 and group 1 was not statistically significant. Results of subgroup analyses in the GO- BEFORE patients were consistent with the primary end point results, including the group of patients with a disease duration 3 years (data not shown). A total of 193 patients (44 in group 1, 58 in group 2, 43 in group 3, and 48 in group 4) had established RA, with a disease duration 3 years. Among these patients, those in the combined groups 3 and 4 had significantly less change in the modified Sharp score from baseline to week 52 (mean 0.62, median 0.0 [interquartile range (IQR) 0.12, 0.50]) as compared with those in group 1 (mean 1.41, median 0.0 [IQR 0.00, 1.50]) (P 0.029). The baseline CRP level (mean 2.2 mg/dl, median 1.20 mg/dl [IQR 0.4, 2.9]), swollen joint count (mean 14.7, median 12.0 [IQR 8.0, 18.0]), and tender joint count (mean 28.8, median 26.0 [IQR 14.0, 39.0]) for this subgroup were similar to those in the GO-BEFORE patient population as a whole. As may be expected given the longer disease duration, the modified Sharp score at baseline in this subgroup of GO-BEFORE patients with a disease duration 3 years (mean 39.2, median 22.0 [IQR 6.0, 55.5]) was higher than that in the GO-BEFORE population as a whole. In another subgroup analysis, mean changes in the modified Sharp score from baseline to week 52 were larger, indicating more radiographic progression, in patients with a CRP of 1.5 mg/dl at screening (1.80 in group 1 and 0.75 in combined groups 3 and 4) than in patients with a CRP of 1.5 mg/dl at screening (0.98 in group 1 and 0.08 in combined groups 3 and 4). In the GO-FORWARD study, the comparator phase continued through week 24, and in patients who entered early escape, their modified Sharp score at week 24 was extrapolated linearly from the baseline and week 16 values. Overall, minimal progression was observed in all treatment groups during this phase, and the differ-

EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA 1207 Figure 3. Probability plots of changes in the total modified Sharp score from baseline in each patient during the portion of the study that included a comparator group. A, Changes in radiographic scores from baseline to week 52 in the GO-BEFORE study patients. B, Changes in radiographic scores from baseline to week 24 in the GO-FORWARD study patients. Upper broken line represents the smallest detectable change for the study (2.7 in the GO-BEFORE study and 1.8 in the GO-FORWARD study); lower broken line represents 0. Insets show the data at both ends of each graph in more detail (i.e., only 0 10% and 90 100%). See Figure 1 for definitions. ences in the changes in modified Sharp scores from baseline between the golimumab groups and placebo were not statistically significant (Figure 2B and Table 2). The individual radiographic scores for each patient are given in the probability plot shown in Figure 3B. Patients in groups 1 and 3 with screening CRP levels that were 1.5 mg/dl showed slightly more radiographic progression at week 24 than did those with screening CRP levels that were 1.5 mg/dl. However, patients in group 4 with a screening CRP level 1.5 mg/dl had a mean change in the modified Sharp score of 0.05, as compared with a mean change of 0.85 in patients in group 1. Changes in erosion and joint space narrowing scores compared with baseline are summarized in Table 3. DISCUSSION We evaluated radiographic progression in two studies of patients with RA who received golimumab: the GO-BEFORE study (in patients who were MTX naive) and the GO-FORWARD study (in patients who had active RA despite MTX therapy). The GO- BEFORE study, which was designed and powered to evaluate radiographic progression as a co-primary end point, demonstrated that golimumab therapy in combination with MTX inhibited radiographic progression significantly better than MTX therapy alone. The difference in radiographic progression between the golimumab monotherapy group and MTX monotherapy group, however, was not statistically significant. Overall, the benefits of the combination of golimumab plus MTX were comparable for the 50-mg and 100-mg dosage groups. In the GO-FORWARD study, minimal radiographic progression was observed in all treatment groups, and no statistically significant differences between the placebo plus MTX group and the golimumab groups with or without MTX were observed. This may have been attributable to the following limitations of the study design and the inclusion/exclusion criteria: first, because radiographic outcomes were only secondary end points in this study, they were not considered in the power calculation assumptions. Second, an elevated CRP level was not required

1208 EMERY ET AL for study entry, and only one-third of patients in this study had CRP levels that were 1.5 mg/dl. Patients with low CRP levels are known to have less radiographic progression over time than those with high CRP levels (10). Third, the placebo-comparator portion of this study continued for only 24 weeks, and the radiographs for patients who entered early escape (nonresponders) were taken at week 16. Since the population consisted mostly of patients whose RA was progressing slowly, the few patients whose RA was most likely to progress were those who entered early escape. However, some of these patients may not have had sufficient progression by week 16 for the readers to detect that progression. Given the low overall progression rate and the short 16-week time period, linear extrapolation from week 16 to week 24 may have underestimated the true progression that these patients would have shown without adjustment in the medication regimen. Fourth, patients who were enrolled in this study generally had less disease activity and radiographic damage at baseline than those in the earlier studies of TNF inhibitors in patients with an inadequate response to MTX (2,11,12). The mean modified Sharp score at baseline in the GO-FORWARD population was 35, as compared with 75 in the Anti Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study of infliximab (11) and with 68 in the study of adalimumab by Keystone and colleagues (12). In a more recent study of certolizumab pegol (13), the mean modified Sharp score at baseline ( 39) was similar to that in the current study, suggesting that the severity of joint damage in the population of patients with RA from which these studies recruited may be decreasing over time (14). Thus, the lack of significant differences between the GO-FORWARD treatment groups may be explained by the above study limitations, as well as by the very limited amount of radiographic progression actually observed in the study population as a whole. We did, however, observe numerically less radiographic progression in the golimumab 100 mg plus MTX group from baseline to week 24, although the possibility that this difference was due to chance cannot be ruled out. The radiographic score and CRP level at baseline have been shown to be predictive of radiographic progression over time (10,15,16). It is likely that the baseline CRP, as a marker of active inflammation in RA, is a more important predictor of radiographic progression than the baseline radiographic score, since radiographic damage is less likely to progress if there is no active inflammation, regardless of the level of damage at baseline. As an example of this phenomenon, patients with RA who had an inadequate response to MTX in the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) study of certolizumab (13) had median baseline CRP levels of 1.6 mg/dl, as compared with 0.9 mg/dl in the GO-FORWARD study. Despite having similar levels of radiographic damage at baseline (modified Sharp scores of 35 in the GO-FORWARD study and 39 in the RAPID 1 study [13]), progression observed in the control group of the RAPID 1 study was greater than that seen in group 1 of the GO- FORWARD study (mean changes in the modified Sharp score from baseline to week 24 1.3 versus 0.6). Similarly, patients in the GO-FORWARD study had more radiographic damage at baseline than those in the GO- BEFORE study. However, patients in the GO- BEFORE study had higher baseline CRP levels and greater radiographic progression during the study than those in the GO-FORWARD study, despite having lower baseline radiographic damage. The relationship between higher CRP level and radiographic progression is further illustrated by the results of the CRP subgroup analyses performed in the GO-BEFORE and GO-FORWARD studies, which generally indicated that more radiographic progression was observed among patients with screening CRP levels that were 1.5 mg/dl versus those with levels that were 1.5 mg/dl. However, while the data discussed herein are consistent with the hypothesis that CRP is a more important predictor of radiographic progression than is the baseline radiographic score, future studies specifically aimed at evaluating this concept are needed. Unlike previous studies of TNF inhibitors in MTX-naive patients with RA (17 19), the GO- BEFORE study permitted the inclusion of patients regardless of disease duration. As a result, approximately one-fourth of the patients in the GO-BEFORE study had disease duration longer than 3 years. This was similar to the disease duration in patients in the GO- FORWARD study and other studies of patients with more established RA (11,20,21), and the patients also had a mean modified Sharp score of 39 at baseline that was similar to the mean baseline score of 35 in the GO-FORWARD population. However, patients in the GO-FORWARD study had evidence of minimal inflammation at baseline, as judged by their lower CRP level, which may have led to minimal radiographic progression in all treatment groups, including the control group. The subgroup of GO-BEFORE patients with disease duration 3 years (more established disease)

EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA 1209 had higher CRP concentrations (median 1.2 mg/dl) and more radiographic progression (mean change in the modified Sharp score from baseline 1.4) was observed in the control group relative to the control group of the GO-FORWARD study (mean change in the modified Sharp score from baseline 0.6). The higher degree of radiographic progression in this subgroup of patients in the GO-BEFORE study allowed the assessment of the effects of golimumab on radiographic progression in patients with more established disease. Patients in this established-disease subgroup of the GO-BEFORE study who received golimumab plus MTX had statistically less radiographic progression than did those who received placebo plus MTX. While both the established-disease subgroup from the GO-BEFORE study and patients from the GO-FORWARD study had established disease and similar radiographic damage at baseline, the baseline level of disease activity (as indicated by CRP level) was higher in the established-disease subgroup from the GO-BEFORE study with 3 years of disease duration. Thus, golimumab effectively inhibited radiographic progression in patients with more established RA when they had higher disease activity and more radiographic progression (in the control group). This again indicates that the minimal progression in the control group of the GO-FORWARD study may have precluded the adequate assessment of the effects of golimumab on radiographic progression. Golimumab has also been shown to inhibit radiographic progression in patients with established psoriatic arthritis, another inflammatory arthritis with similar mechanisms of joint erosion (22), who had an inadequate response to conventional therapies, including MTX (23). In conclusion, minimal radiographic progression was observed in all treatment arms of the GO- FORWARD study, which precluded adequate assessment of the effects of golimumab on radiographic progression in patients with established disease. Results of the GO-BEFORE study showed that golimumab plus MTX inhibited radiographic progression not only in patients with early RA, but also in a subset of patients with more established disease ( 3 years). ACKNOWLEDGMENTS We thank the patients, investigators, and study personnel who made these trials possible. We also thank Scott Newcomer (formerly of Centocor Ortho Biotech Inc.) and Michelle Perate (Centocor Ortho Biotech Inc.) who helped prepare the manuscript. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Emery had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Emery, Fleischmann, van der Heijde, Keystone, Genovese, Conaghan, Hsia, Xu, Baratelle, Rahman. Acquisition of data. Emery, Fleischmann, Genovese, Hsia, Xu, Baratelle, Beutler, Rahman. Analysis and interpretation of data. Emery, Fleischmann, van der Heijde, Keystone, Genovese, Conaghan, Hsia, Xu, Beutler, Rahman. ROLE OF THE STUDY SPONSOR Centocor Research and Development, Inc. (a subsidiary of Johnson & Johnson) and Schering-Plough/Merck Research Institute, Inc. sponsored this study. The following steering committee members who were also authors of this article assisted Centocor scientists with the study design and conduct: Paul Emery, MA, MD, FRCP, Roy M. Fleischmann, MD, Edward C. Keystone, MD, FRCP, and Mark C. Genovese, MD. Data were collected by the investigators and entered into a Centocor database. Centocor statisticians and programmers conducted the analyses, and members of the steering committee, with the assistance of medical writers Scott Newcomer (formerly of Centocor Ortho Biotech Inc.) and Michelle Perate (Centocor Ortho Biotech Inc., a wholly owned subsidiary of Johnson & Johnson, Inc.), prepared the manuscript. All authors reviewed and approved the manuscript content before submission and jointly agreed to submit the final version of the manuscript. Publication of this study was not contingent upon approval from Centocor or Schering-Plough/Merck. REFERENCES 1. Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, et al. 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