L. Kim

Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study.

OBJECTIVE To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). METHODS Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15-25 mg/week for > or = 4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. RESULTS The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). CONCLUSION The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns.

Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial

Objectives Evaluate the efficacy of intravenous golimumab 2 mg/kg+methotrexate (MTX) in patients with active rheumatoid arthritis (RA) receiving MTX. Methods Patients (n=592) with active disease (≥6/66 swollen, ≥6/68 tender joints, C-reactive protein ≥1.0 mg/dl, rheumatoid factor positive and/or anticyclic citrullinated protein antibody positive at screening) despite MTX (15–25 mg/week) participated in this double-blind, placebo-controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg, or placebo infusions at weeks 0 and 4 and every (q) 8 weeks; patients continued MTX. Placebo patients with <10% improvement in combined swollen/tender joint counts at week 16 could early escape to intravenous golimumab 2 mg/kg. The primary endpoint was week 14 American College of Rheumatology 20% (ACR20) response. Analyses employed non-responder imputation and last-observation-carried-forward. Results At week 14, significantly (p<0.001) larger proportions of golimumab+MTX than placebo+MTX patients achieved ACR20 response (59% vs 25%, respectively), a disease activity score of good/moderate (EULAR) response (81% vs 40%), and greater median improvement in health assessment questionnaire scores (0.500 vs 0.125). Improvements versus placebo+MTX were observed by week 2. Similar proportions of patients receiving golimumab+MTX and placebo+MTX, respectively, reported adverse events through week 16 (47% and 44%) and week 24 (53% and 49%). Serious adverse events were reported by more golimumab+MTX (4.1%) than placebo+MTX (2%) patients at week 24. Conclusion The addition of intravenous golimumab rapidly and significantly improved signs and symptoms in patients with active RA despite ongoing MTX, in some patients by week 2.

Radiographic benefit and maintenance of clinical benefit with intravenous golimumab therapy in patients with active rheumatoid arthritis despite methotrexate therapy: results up to 1 year of the phase 3, randomised, multicentre, double blind, placebo controlled GO-FURTHER trial

Objective Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). Methods Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15–25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; <10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here. Results Significant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p<0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a ‘good’ or ‘moderate’ response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections. Conclusions In patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year. ClinicalTrials.gov NCT00973479, EudraCT 2008–006 064–11.

Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial

Objective This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). Methods In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0–16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16–48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. Results Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. Conclusion Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. Clinical Trial Registration NCT01230827; Results.

The Effect of Intravenous Golimumab on Health-related Quality of Life in Rheumatoid Arthritis: 24-week Results of the Phase III GO-FURTHER Trial

Objective. To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy. Methods. In this randomized, multicenter, double-blind, placebo-controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. All patients continued stable oral MTX (15–25 mg/wk). HRQOL assessments included Health Assessment Questionnaire-Disability Index (HAQ-DI; physical function), Medical Outcomes Study Short Form-36 questionnaire physical/mental component summary (SF-36 PCS/MCS) scores, EQ-5D assessment of current health state, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, and disease effect on productivity [10-cm visual analog scale (VAS)]. Results. Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p < 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p < 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p < 0.001) and FACIT-Fatigue (p < 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p < 0.001). Improvements in physical function, HRQOL, fatigue, and productivity significantly correlated with disease activity improvement. Conclusion. In active RA, IV golimumab + MTX significantly improved physical function, HRQOL, fatigue, and productivity using multiple measurement tools; all correlated with improvements in disease activity (NCT00973479, EudraCT 2008-006064-11).

Maintenance of efficacy and safety with subcutaneous golimumab among patients with active rheumatoid arthritis who previously received intravenous golimumab.

Objective. To evaluate the efficacy/safety of subcutaneous (SC) golimumab in patients with rheumatoid arthritis (RA) who previously received intravenous (IV) golimumab with or without methotrexate (MTX). Methods. Adult patients with RA (n = 643) with persistent disease despite MTX (≥ 15 mg/wk for ≥ 3 months) were randomized to IV placebo + MTX (n = 129) or IV golimumab 2–4 mg/kg (± MTX) every 12 weeks (n = 514). Patients who completed the study through Week 48 could participate in the longterm extension (LTE), comprising open-label golimumab 50 mg SC every 4 weeks (± MTX) for 24 weeks (LTE-0 to LTE-24) followed by 16 weeks of safety followup (LTE-24 to LTE-40; MTX could be adjusted). Results. At Week 48, 28% (nominal p < 0.001 vs placebo), 11%, and 8% of patients who received IV golimumab + MTX, golimumab alone, and placebo + MTX, respectively, achieved ≥ 50% improvement in the American College of Rheumatology response criteria (ACR50). Among the 505 patients who entered the LTE and were still participating, the proportion of patients treated with golimumab 50 mg SC (± MTX) achieving an ACR50 response increased to 44% at both LTE-14 and LTE-24. ACR20, ACR70, and 28-joint Disease Activity Score using C-reactive protein exhibited similar response patterns as ACR50. Infections were the most commonly reported adverse events through the end of IV golimumab dosing (37% placebo + MTX, 45% golimumab, 51% golimumab + MTX) and with SC golimumab from LTE-0 through LTE-40 (35% golimumab, 36% golimumab + MTX). Concomitant MTX use yielded lower incidences of antibodies to SC golimumab and injection-related reactions. Conclusion. Clinical improvements observed in golimumab-treated patients were sustained or improved in patients switched from IV (2–4 mg/kg ± MTX) to open-label SC (50 mg ± MTX) golimumab. Both IV and SC golimumab demonstrated acceptable safety profiles (Clinicaltrials.gov NCT00361335).

Safety and Efficacy of Intravenous Golimumab in Patients With Active Psoriatic Arthritis

To evaluate the safety and efficacy of intravenous (IV) golimumab treatment in psoriatic arthritis (PsA).

FRI0266 Health-Related Quality of Life of Patients with Rheumatoid Arthritis Achieving DAS28 Remission, Improvement in Physical Function and NO Radiographic Progression after Treatment with Intravenous Golimumab

Objectives To evaluate “comprehensive remission” in patients with rheumatoid arthritis (RA) treated with intravenously administered golimumab (GLM) and the association with normalized health related quality of life (HRQOL). Methods GO-FURTHER was a multicenter, randomized, placebo-controlled study. Adult patients with active RA despite MTX therapy (≥6 tender and swollen joints, CRP ≥1.0 mg/dL, and RF and/or anti-CCP positive) were randomized to placebo (PBO) + MTX or GLM (2mg/kg) plus MTX at week 0, 2, and every 8 week thereafter (GLM group). Patients in PBO group with <10% improvement in tender and swollen joint count from baseline at week 16 entered early escape (EE) and received a 2 mg/kg GLM infusion at weeks 16 and 20 and every 8 weeks subsequent. HRQOL was assessed using Short-Form of 36 items questionnaire (SF-36) and FACIT-fatigue. Employability was defined as being employed or to be able to work if job is available. Radiographic progression was measured using Total Sharp score (TSS). “Comprehensive remission” was defined as achieving low disease activity score (DAS28 using CRP <2.6), normalized physical function (HAQ-DI≤0.5) and no radiographic progression (change in TSS ≤ Smallest detectable change). Remission was also assessed using criteria of Simplified Disease Activity Index (SDAI, ≤3.3). Results Compared to PBO+MTX group at week 24, greater proportion of patients in GLM IV group achieved DAS28<2.6 (17.7% vs. 5.1%, p<0.001), HAQ-DI score≤0.5 (29.4% vs. 16.2%, p<0.001) or no radiographic progression (91.4% vs. 80.7%, p<0.001). “Comprehensive remission” rate was 10.1% in GLM group vs. 2.5% in PBO+MTX group (p=0.001). Additionally, SDAI remission at week 24 was 7.6% in GLM group vs. 2.0% in PBO+MTX group (P<0.01).”Comprehensive remission” was sustained in the GLM group over time at week 52 (12.4%) or week 100-112 (15.4%). Compared to patients who achieved DAS28 remission or SDAI remission, patients who achieved “comprehensive remission” at week 24 achieved numerically greater improvement in normalized HRQOL in SF-36 PCS and MCS and in FACIT-fatigue, and were more likely regain employability at Week 24, 52 or week 112. Conclusions By taking into consideration of outcomes reported by clinician and patient, and radiographic progression, “comprehensive remission” might be a more desirable treatment goal for patients with RA. Disclosure of Interest R. Westhovens Grant/research support: Janssen R & D, LLC, M. Weinblatt Grant/research support: Janssen R & D, LLC, C. Han Employee of: Janssen Pharmaceutical Services, LLC, L. Kim Employee of: Janssen R & D, LLC, M. Mack Employee of: Janssen R & D, LLC, J. Lu Employee of: Janssen R & D, LLC, D. Baker Employee of: Janssen R & D, LLC, A. Mendelsohn Employee of: Janssen R & D, LLC, C. Bingham III Grant/research support: Janssen R & D, LLC, Consultant for: Janssen R & D, LLC DOI 10.1136/annrheumdis-2014-eular.3819

Maintenance of Clinical and Radiographic Benefit With Intravenous Golimumab Therapy in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy: Week-112 Efficacy and Safety Results of the Open-Label Long-Term Extension of a Phase III, Double-Blind, Randomized, Placebo-Controlled Trial.

To evaluate the safety, efficacy, pharmacokinetics, immunogenicity, and radiographic progression through 2 years of treatment with intravenous (IV) golimumab plus methotrexate (MTX) in an open‐label extension of a phase III trial of patients with active rheumatoid arthritis (RA) despite MTX therapy.

THU0153 Hemoglobin Is A Better Predictor for Radiographic Progression than Das28 in Patients with Moderate To Severe Rheumatoid Arthritis-Analysis from Intravenously Administered Golimumab Go-Further Study

Background Clinical studies demonstrated that baseline disease activity including C-reactive protein (CRP) level was a predictor variable for radiographic joint damage in patients with rheumatoid arthritis (RA). Objectives To identify variables associated with radiographic joint damage in patients with RA treated with intravenously administered golimumab (GLM) + Methotrexate (MTX) or MTX + placebo (PBO). Methods GO-FURTHER was a multicenter, randomized, placebo-controlled study. Adult patients with active RA despite MTX therapy (≥6 tender and swollen joints, CRP ≥1.0 mg/dL, and RF and/or anti-CCP positive) were randomized to placebo (PBO) + MTX or GLM (2mg/kg) plus MTX at week 0, 2, and every 8 week thereafter (GLM group). Patients in PBO group with <10% improvement in tender and swollen joint count from baseline at week 16 entered early escape (EE) and received a 2 mg/kg GLM infusion at weeks 16 and 20 and every 8 weeks subsequent. Radiographic progression was measured using Total Sharp score (TSS). The correlations of TSS with hemoglobin, disease activity score (DAS28-CRP)and physical function evaluated with Health Assessment Questionnaire (HAQ) were assessed using Spearmans correlation or multivariable liner regression model. Anemia was defined based on World Health Organization (WHO) criteria as Hgb <12 g/dl in women and <13 g/dl in men. Results Moderate to severe RA was demonstrated by a mean DAS28 score of 5.9 with TSS of 48.5 in all patients group at baseline. In linear regression models, baseline DAS28, HAQ score, and Hgb level was correlated with baseline TSS with Spearmans correlation coefficient (r) of 0.148 (p<0.01), 0.0.193 (p<0.001) and -0.129 (p<.001), respectively. Similar correlation relationships of TSS score with DAS28, HAQ and Hgb were observed at Week 24. In multiple linear regression models, after adjusting for effect of other factors, Hgb level demonstrated significant correlation with TSS at the baseline or Week 24. The change in Hgb at Week 20 also was correlated with change in TSS at Week 24 after adjusting for change in DAS28 and HAQ. GLM IV + MTX-treated patients demonstrated less radiographic damage than MTX+PBO-treated patients regardless of their anemia status at baseline or week 20. Conclusions Hemoglobin level is an independent variable predicting radiographic progression in MTX refractory RA patients. Disclosure of Interest R. Westhovens Grant/research support from: Janssen R & D, LLC, C. Han Employee of: Johnson & Johnson Pharmaceutical Services, LLC, M. Weinblatt Grant/research support from: Janssen R & D, LLC, L. Kim Employee of: Janssen R & D, LLC, E. Hsia Employee of: Janssen R & D, LLC, D. Parenti Employee of: Janssen Scientific Affairs, LLC, S. Kafka Employee of: Janssen Scientific Affairs, LLC, C. Bingham III Grant/research support from: Janssen R & D, LLC