Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

Outcomes in Adult Inflammatory Bowel Disease Clinical Trials: Assessment of Similarity Among Participants with Adolescent-Onset and Adult-Onset Disease.

BACKGROUND AND AIMS: Most pediatric IBD studies are performed after medications are approved in adults and the majority of participants in these studies are adolescents. We hypothesized that adolescent-onset IBD is not fundamentally different than adult-onset IBD. If this is correct, the value of delaying access to novel drugs in adolescents becomes questioned. METHODS: Data from 11 randomized, double-blind, placebo-controlled adult phase 2 and 3 trials of 4 biologics were analyzed. Participants were categorized as having adolescent- or adult-onset disease (diagnosed 12 to <18, or ≥18 years). Multivariable modelling explored the association between age at diagnosis and response to treatment after adjustment for disease duration, extent, and severity at baseline. Data from dose arms were pooled to evaluate similarity of therapeutic response between adolescent- and adult-onset IBD within the same trial (not between doses or across trials). Ratios of odds ratios between the two groups were evaluated. RESULTS: Data from 6,283 study participants (2,575 with Crohn's disease [CD], 3,708 with ulcerative colitis [UC]) were evaluated. Of 2,575 study participants with CD, 325 were 12-<18 years old at diagnosis; 836 participants (32.4%) received placebo. Of 3,708 participants with UC, 221 were 12-<18 years old at diagnosis; 1,212 (33%) were receiving placebo. The majority of the ratios of ORs were within two-fold, suggesting that responses in adolescent and adult-onset participants are generally similar. CONCLUSION: Data presented lend support for extrapolating efficacy of biologics from adults to adolescents with IBD, which would facilitate earlier labeling and patient access.

Effect of Intravenous Golimumab on Fatigue and the Relationship with Clinical Response in Adults with Active Ankylosing Spondylitis in the Phase 3 GO-ALIVE Study.

INTRODUCTION: We studied the effect of intravenous (IV)-golimumab on fatigue and the association of fatigue improvement with clinical response post hoc in adults with active ankylosing spondylitis (AS) in the GO-ALIVE trial. METHODS: Patients were randomized to IV-golimumab 2 mg/kg (N = 105) at week (W) 0, W4, then every 8 W (Q8W) or placebo (N = 103) at W0, W4, W12, crossover to IV-golimumab 2 mg/kg at W16, W20, then Q8W through W52. Fatigue measures included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question #1 (fatigue; 0 [none], 10 [worst]; decrease indicates improvement) and 36-Item Short Form Health Survey (SF-36) vitality subscale (0 [worst], 100 [best]; increase indicates improvement). Minimum clinically important difference is ≥ 1 for BASDAI-fatigue and ≥ 5 for SF-36 vitality. GO-ALIVE primary endpoint was Assessment of SpondyloArthritis international Society ≥ 20% improvement criteria (ASAS20). Other clinical outcomes assessed included other ASAS responses, Ankylosing Spondylitis Disease Activity Score, and Bath Ankylosing Spondylitis Functional Index score. The distribution-based minimally important differences (MIDs) were determined for BASDAI-fatigue and SF-36 vitality. The relationship between improvement in fatigue and clinical outcomes was assessed via multivariable logistic regression. RESULTS: Mean changes in BASDAI-fatigue/SF-36 vitality scores were greater with IV-golimumab versus placebo at W16 (- 2.74/8.46 versus - 0.73/2.08, both nominal p ≤ 0.003); by W52 (after crossover), differences between groups narrowed (- 3.18/9.39 versus - 3.07/9.17). BASDAI-fatigue/SF-36 vitality MIDs were achieved by greater proportions of IV-golimumab-treated versus placebo-treated patients at W16 (75.2%/71.4% versus 42.7%/35.0%). A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 increased likelihood of achieving ASAS20 (odds ratios [95% confidence intervals]: 3.15 [2.21, 4.50] and 2.10 [1.62, 2.71], respectively) and ASAS40 (3.04 [2.15, 4.28] and 2.24 [1.68, 3.00], respectively) responses at W16; concurrent improvements and clinical response at W52 were consistent. A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 predicted increased likelihood of achieving ASAS20 (1.62 [1.35, 1.95] and 1.52 [1.25, 1.86], respectively) and ASAS40 (1.62 [1.37, 1.92] and 1.44 [1.20, 1.73], respectively) responses at W52. CONCLUSIONS: IV-golimumab provided important and sustained fatigue improvement in patients with AS that positively associated with achieving clinical response. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02186873.

Ankylosing spondylitis (AS) is a type of arthritis that mostly affects the spine. Patients with AS also often have severe fatigue. Intravenous (IV)-golimumab, which blocks the inflammatory action of tumor necrosis factor, is approved to treat AS. We used information from a clinical trial (GO-ALIVE) to determine whether IV-golimumab reduced fatigue in patients with AS, and if fatigue improvement was associated with improvement in other AS symptoms, including spinal pain, ability to function, and inflammation. In the 1-year GO-ALIVE study, patients were assigned to receive either IV-golimumab or placebo. Patients assigned to placebo were switched to IV-golimumab starting at week 16. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue question and the 36-Item Short Form Health Survey (SF-36) vitality subscale were used to assess fatigue. Improvement in AS symptoms was measured using the Assessment of SpondyloArthritis international Society ≥ 20% and ≥ 40%  improvement criteria (ASAS20 and ASAS40). After 16 weeks of treatment, patients treated with IV-golimumab, on average, had statistically significantly greater improvement in both measures of fatigue than patients treated with placebo. At 1 year, after the placebo group had received IV-golimumab starting at week 16, improvement in fatigue was similar between groups. Improvement in fatigue at week 16 increased the likelihood that ASAS20 and ASAS40 would be achieved at week 16. Similar results were observed at 1 year. Additionally, improvement in fatigue at week 16 predicted the likelihood of achieving ASAS20 and ASAS40 at 1 year. Together, these results demonstrate that IV-golimumab provided important, long-term improvement in fatigue in patients with AS that was positively associated with improvement in AS symptoms.

The effect of intravenous golimumab on health-related quality of life and work productivity in patients with active psoriatic arthritis: results of the Phase 3 GO-VIBRANT trial.

INTRODUCTION/OBJECTIVES: To evaluate changes in health-related quality of life (HRQoL) and productivity following treatment with intravenous (IV) golimumab in patients with psoriatic arthritis (PsA). METHODS: Patients were randomized to IV golimumab 2 mg/kg (n=241) at Weeks 0, 4, then every 8 weeks (q8w) through Week 52 or placebo (n=239) at Weeks 0, 4, then q8w, with crossover to IV golimumab 2 mg/kg at Weeks 24, 28, then q8w through Week 52. Change from baseline in EuroQol-5 dimension-5 level (EQ-5D-5L) index and visual analog scale (EQ-VAS), daily productivity VAS, and the Work Limitations Questionnaire (WLQ) was assessed. Relationships between these outcomes and disease activity and patient functional capability were evaluated post hoc. RESULTS: At Week 8, change from baseline in EQ-5D-5L index (0.14 vs 0.04), EQ-VAS (17.16 vs 3.69), daily productivity VAS (-2.91 vs -0.71), and WLQ productivity loss score (-2.92 vs -0.78) was greater in the golimumab group versus the placebo group, respectively. At Week 52, change from baseline was similar in the golimumab and placebo-crossover groups (EQ-5D-5L index: 0.17 and 0.15; EQ-VAS: 21.61 and 20.84; daily productivity VAS: -2.89 and -3.31; WLQ productivity loss: -4.49 and -3.28, respectively). HRQoL and productivity were generally associated with disease activity and functional capability, with continued association from Week 8 through Week 52. CONCLUSION: IV golimumab resulted in early and sustained improvements in HRQoL and productivity from Week 8 through 1 year in patients with PsA. HRQoL and productivity improvements were associated with improvements in disease activity and patient functional capability. Key Points • In patients with active psoriatic arthritis (PsA), intravenous (IV) golimumab improved health-related quality of life (HRQoL) and productivity as early as 8 weeks and maintained improvement through 1 year • Improvements in HRQoL and productivity outcomes in patients with PsA treated with IV golimumab were associated with improvements in disease activity and patient functional capability outcomes • IV golimumab is an effective treatment option for PsA that can mitigate the negative effects of the disease on HRQoL and productivity.

The effect of intravenous golimumab on health-related quality of life and work productivity in adult patients with active ankylosing spondylitis: results of the phase 3 GO-ALIVE trial.

INTRODUCTION/OBJECTIVES: The effect of intravenous (IV) golimumab on health-related quality of life (HRQoL) and productivity in patients with ankylosing spondylitis (AS) was evaluated. METHOD: Patients were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, then every 8 weeks (q8w) through week 52 or placebo (n = 103) at weeks 0, 4, 12, with crossover to golimumab 2 mg/kg at weeks 16, 20, then q8w through week 52. Changes from baseline in EuroQol-5 dimension-5 level (EQ-5D-5L) index and visual analog scale (EQ-VAS), daily productivity VAS, Work Limitations Questionnaire (WLQ), and Ankylosing Spondylitis Quality of Life (ASQoL) were assessed. Correlations between these outcomes and disease activity and patient functioning outcomes were evaluated post hoc. RESULTS: At week 16, changes from baseline (mean ± standard deviation) in EQ-5D-5L index (0.17 ± 0.16 vs 0.05 ± 0.14), EQ-VAS (20.3 ± 24.6 vs 4.8 ± 23.5), daily productivity VAS (- 2.9 ± - 2.9 vs - 1.1 ± - 2.5), WLQ productivity loss score (- 3.5 ± - 5.3 vs - 1.9 ± - 4.0), and ASQoL (- 5.4 ± - 5.0 vs - 1.8 ± - 4.5) were greater in the IV golimumab versus placebo group, respectively. At week 28, changes from baseline were similar between the IV golimumab and placebo-crossover groups (EQ-5D-5L index: 0.18 ± 0.17 and 0.16 ± 0.16, EQ-VAS: 20.5 ± 27.9 and 22.5 ± 23.1, daily productivity VAS: - 3.1 ± - 3.0 and - 3.1 ± - 2.8, WLQ productivity loss: - 3.9 ± - 5.5 and - 4.5 ± - 4.5, and ASQoL: - 5.3 ± - 5.2 and - 5.3 ± - 4.8, respectively); improvements were maintained through week 52. HRQoL and productivity outcomes were generally moderately correlated with disease activity and functioning outcomes. CONCLUSIONS: In patients with AS, IV golimumab produced sustained improvements in HRQoL and productivity through 1 year, which correlated with improvements in disease activity and functioning. ClinicalTrials.gov registry number is NCT02186873. Key Points • Intravenous (IV) golimumab resulted in clinically important improvement in general and ankylosing spondylitis-specific health-related quality of life (HRQoL) and productivity outcomes in patients with ankylosing spondylitis (AS) as early as week 8 and maintained improvement through 1 year • Improvements in HRQoL and productivity outcomes in these patients with AS were correlated with improvements in measures of disease activity and patient functional capability • IV golimumab is an effective treatment option for AS that can help mitigate the negative effects of the disease on HRQoL and productivity.

Effects of Intravenous Golimumab on Health-Related Quality of Life in Patients with Ankylosing Spondylitis: 28-Week Results of the GO-ALIVE Trial.

OBJECTIVE: Evaluate the effect of intravenous golimumab on health-related quality of life (HRQoL) in patients with ankylosing spondylitis (AS) through week 28 of the phase III, multicenter, randomized, double-blind, placebo-controlled GO-ALIVE study. METHODS: Adult patients (n = 208) were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, and 12 and every 8 weeks or placebo (n = 103) at weeks 0, 4, and 12, with crossover to golimumab 2mg/kg at weeks 16, 20, and every 8 weeks. General HRQoL was evaluated using the Short Form Health Survey (SF-36) Physical Component Summary/Mental Component Summary (PCS/MCS), and the EQ VAS, and AS disease-specific HRQoL was assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) instrument. RESULTS: Mean improvements from baseline in SF-36 PCS were greater in the golimumab group versus the placebo group at weeks 8 and 16 (6.8 vs 2.1 and 8.5 vs 2.9, respectively; P < .001); similar results were observed for SF-36 MCS (5.6 vs 1.7 and 6.5 vs 0.8, respectively; P < .001). Mean improvement in each of 8 subscale scores of the SF-36 were also greater for golimumab-treated patients versus placebo at weeks 8 and 16. Mean improvements in EQ VAS and ASQoL were greater in the golimumab group versus placebo at week 8 and week 16. Greater proportions of golimumab-treated patients had clinically meaningful improvement in SF-36 PCS, SF-36 MCS, EQ VAS, and ASQoL at weeks 8 and 16; improvements in SF-36 PCS/MCS, EQ VAS, and ASQoL were maintained through week 28. CONCLUSIONS: Golimumab-treated patients had greater mean improvements in HRQoL measures compared with placebo through week 16. Clinically meaningful improvements were observed as early as week 8 and continued through week 28.

Effects of Intravenous Golimumab on Health-Related Quality of Life in Patients With Psoriatic Arthritis: 24-Week Results of the GO-VIBRANT Trial.

OBJECTIVES: Evaluate the effects of intravenous golimumab 2 mg/kg on multiple domains of health-related quality of life (HRQoL) in adult patients with active psoriatic arthritis (PsA). METHODS: In this phase III, randomized, double-blinded, placebo-controlled study, adults with active PsA were randomized in a 1:1 ratio to receive intravenous (IV) infusions of placebo (n = 239) or golimumab 2 mg/kg (n = 241) at weeks 0, 4, 12, and 20. Physical function was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI). HRQoL was assessed using the 36-item Short-Form Health Survey Physical and Mental Component Summary (SF-36 PCS/MCS) scores, the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, EQ VAS, and the Dermatology Life Quality Index (DLQI). RESULTS: Patients in the golimumab group had greater mean changes from baseline in HAQ-DI compared with placebo at weeks 8 (-0.52 vs -0.10), 14 (-0.60 vs -0.12), and 24 (-0.63 vs -0.14). Mean improvements from baseline in SF-36 PCS (8.0 vs 1.7), SF-36 MCS (5.0 vs 1.2), EQ VAS (17.2 vs 3.7), FACIT-Fatigue (7.9 vs 2.0), and DLQI (-7.2 vs -1.7) were also greater in the golimumab group versus placebo at week 8 and were maintained or increased through week 24. Greater proportions of golimumab-treated patients had improvements greater than or equal to the minimal clinically important difference (MCID) for HAQ-DI, SF-36 PCS/MCS, EQ VAS, FACIT-Fatigue, and DLQI scores at weeks 14 and 24. CONCLUSION: Improvements in HRQoL were greater in the IV golimumab group compared with placebo and were evident at week 8 and sustained through week 24.

Evaluation of Improvement in Skin and Nail Psoriasis in Bio-naïve Patients With Active Psoriatic Arthritis Treated With Golimumab: Results Through Week 52 of the GO-VIBRANT Study.

OBJECTIVE: To evaluate whether intravenous (IV) golimumab produces improvements in skin and nail symptoms that are concomitant with improvements in quality of life (QoL) and joint symptoms in patients with psoriatic arthritis. METHODS: Patients were randomized to either IV golimumab 2 mg/kg at weeks 0, 4, then every 8 weeks (q8w) through week 52 or placebo at weeks 0, 4, then q8w, with crossover to IV golimumab 2 mg/kg at weeks 24, 28, and then q8w through week 52. Assessments included Psoriasis Area and Severity Index (PASI), modified Nail Psoriasis Severity Index (mNAPSI), Dermatology Life Quality Index (DLQI), and American College of Rheumatology (ACR) rheumatoid arthritis response criteria. RESULTS: Through week 24, achievement of PASI 75/90/100 responses (P ≤ .0098) and mean improvements in mNAPSI (-11.4 vs -3.7; P < .0001) and DLQI (-9.8 vs -2.9; P < .0001) were significantly greater with golimumab versus placebo. Responses were maintained in patients treated with golimumab through week 52. In placebo-crossover patients, increases in the proportion of patients achieving PASI 75/90/100 responses were observed from weeks 24 to 52, and mean improvements in mNAPSI (from -3.7 to -12.9) and DLQI (from -2.9 to -7.8) increased from weeks 24 to 52. Simultaneous achievement of PASI and DLQI responses, PASI and ACR responses, and mNAPSI and DLQI responses were also observed. Similar responses were observed for all assessments regardless of concomitant methotrexate use. CONCLUSION: Improvements in skin and nail psoriasis symptoms with IV golimumab in patients with psoriatic arthritis were concomitant with improvements in QoL and arthritis disease activity through 1 year.

Efficacy and Safety of Intravenous Golimumab Through One Year in Patients With Active Psoriatic Arthritis.

OBJECTIVE: The present study was undertaken to evaluate the safety and efficacy of intravenous (IV) golimumab in patients with active psoriatic arthritis (PsA) through 1 year. METHODS: GO-VIBRANT was a phase III, randomized, placebo-controlled trial of 480 adults with active PsA. Patients were randomized to receive IV placebo (n = 239) or golimumab 2 mg/kg (n = 241) at weeks 0, 4, and every 8 weeks, with placebo crossover to golimumab at weeks 24, 28, and every 8 weeks thereafter. Efficacy through week 52 was assessed using the American College of Rheumatology (ACR) ≥20%, 50%, or 70% improvement criteria (ACR20/50/70), and the Psoriasis Area and Severity Index ≥75% improvement criteria (PASI75). Radiographic progression was measured using the PsA-modified Sharp/van der Heijde score (SHS). Adverse events (AEs) were monitored through week 60. RESULTS: The primary and major secondary end points through week 24 were achieved. At week 52, 76.8% of patients in the golimumab group and 77.0% in the placebo-crossover group achieved an ACR20 response, 58.1% and 53.6%, respectively, achieved an ACR50 response, and 38.6% and 33.9%, respectively, achieved an ACR70 response. Among patients with ≥3% body surface area affected, 71.9% in the golimumab group and 60.6% in the placebo-crossover group achieved a PASI75 response at week 52. Mean change from baseline in total SHS at week 52 was -0.5 in the golimumab group and 0.8 in the placebo-crossover group. Through week 60, 50.9% of all golimumab-treated patients had ≥1 AE, and 5.2% had ≥1 serious AE. There were no opportunistic infections, 2 malignancies, and 1 death in patients treated with golimumab. CONCLUSION: Sustained improvements in joint and skin disease in patients with PsA were maintained through 1 year in the GO-VIBRANT study. No new safety signals for IV golimumab were identified.

Safety and Efficacy of Intravenous Golimumab in Adults with Ankylosing Spondylitis: Results through 1 Year of the GO-ALIVE Study.

OBJECTIVE: Evaluate safety and efficacy of intravenous (IV) golimumab (GOL) in patients with active ankylosing spondylitis (AS) through 1 year. METHODS: A total of 208 patients were randomized to IV infusions of GOL 2 mg/kg (n = 105) at weeks 0, 4, and every 8 weeks thereafter or placebo (n = 103) at weeks 0, 4, and 12, then crossover to GOL at weeks 16, 20, and every 8 weeks thereafter through Week 52. Efficacy was assessed using the Assessment of Spondyloarthritis international Society (ASAS) criteria, the Ankylosing Spondylitis Disease Activity Score (ASDAS), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Bath Ankylosing Spondylitis Functional Index (BASFI). Health-related quality of life was assessed using the AS Quality of Life (ASQoL) index. Efficacy and safety were monitored through Week 52 and Week 60, respectively. RESULTS: The primary endpoint (ASAS20) and all controlled endpoints at Week 16 were achieved. At Week 52, 69.5% and 65.0% of patients in the GOL group and placebo crossover group, respectively, achieved an ASAS20; 56.2% and 51.5% achieved an ASAS40; 56.2% and 55.3% achieved a BASDAI50; 24.8% and 24.3% achieved ASAS partial remission; and 25.7% and 26.2% met ASDAS inactive disease criteria (all last observation carried forward). Mean changes from baseline to Week 52 in BASFI and ASQoL scores were similar between the GOL group and the placebo crossover group (BASFI: -2.7 and -2.6; ASQoL: -5.5 and -5.4). Through Week 60, 55.4% of all GOL-treated patients had ≥ 1 adverse events (AE); 3.4% had ≥ 1 serious AE. CONCLUSION: Efficacy was maintained through 1 year with IV GOL 2 mg/kg among patients with active AS. AE were consistent with the known safety profile of GOL.

Radiographic Progression Inhibition with Intravenous Golimumab in Psoriatic Arthritis: Week 24 Results of a Phase III, Randomized, Double-blind, Placebo-controlled Trial.

OBJECTIVE: Evaluate effects of intravenous (IV) golimumab (GOL) on radiographic progression in psoriatic arthritis (PsA). METHODS: This phase III, randomized, double-blind, placebo-controlled trial (GO-VIBRANT) randomized patients with active PsA to receive IV placebo (n = 239) or IV GOL 2 mg/kg (n = 241) at weeks 0, 4, 12, and 20. Radiographic progression (controlled secondary endpoint) was evaluated as change from baseline at Week 24 in PsA-modified total Sharp/van der Heijde scores (SvdH). The proportions of patients with a change from baseline at Week 24 in the total PsA-modified SvdH exceeding the smallest detectable change (SDC) or > 0 or 0.5 also were determined. RESULTS: Overall, 474 patients (237/arm) contributed radiographic data. Results obtained from the 2 blinded, independent radiographic readers demonstrated good agreement (total score intraclass correlation coefficients: baseline = 0.93, Week 24 = 0.92, Week 24 change score = 0.73). GOL demonstrated significant inhibition of radiographic progression relative to placebo from baseline to Week 24 (mean changes in PsA-modified total SvdH: -0.36 vs 1.95; treatment difference: -2.32; p < 0.001). At Week 24, smaller proportions of GOL- versus placebo-treated patients demonstrated an increase in the total PsA-modified SvdH score exceeding the SDC (8.0% vs 27.0%, respectively; difference: -19.0%; p < 0.001), > 0 (28.3% vs 57.0%, respectively; difference: -28.7%; p < 0.001), or > 0.5 (18.6% vs 41.8%, respectively; difference: -23.2%; p < 0.001). Results were consistent for erosion and joint space narrowing scores, in hands and feet, and in patients with/without baseline concomitant methotrexate use. Prevention of radiographic progression by GOL was independent of clinical response. CONCLUSION: IV GOL is significantly better than placebo in inhibiting radiographic progression of structural damage in active PsA. [Clinical trial registration number (www.ClinicalTrials.gov): NCT02181673].

Gene Expression Signature for Prediction of Golimumab Response in a Phase 2a Open-Label Trial of Patients With Ulcerative Colitis.

Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961.

Safety and Efficacy of Golimumab Administered Intravenously in Adults with Ankylosing Spondylitis: Results through Week 28 of the GO-ALIVE Study.

OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab (GOL) in patients with active ankylosing spondylitis (AS). METHODS: In a phase III, randomized, double-blind, placebo (PBO)-controlled trial, 208 patients were randomized (1:1) to intravenous (IV) infusions of GOL 2 mg/kg (n = 105) at weeks 0, 4, 12, and every 8 weeks, or PBO (n = 103) at weeks 0, 4, and 12, with crossover to GOL at Week 16. The primary endpoint was ≥ 20% improvement from baseline in the Assessment of Spondyloarthritis International Society Criteria (ASAS20) at Week 16. Secondary endpoints included ASAS40, ≥ 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), and change in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 16. Safety was monitored through Week 28. RESULTS: Significantly greater proportions of GOL-treated patients had ASAS20 response at Week 2 (37.1% vs 19.4%; p = 0.005) and at Week 16 (73.3% vs 26.2%; p < 0.001). At Week 16, 41.0% of those receiving GOL achieved BASDAI50 compared with 14.6% of those taking PBO (p < 0.001), and the GOL group had greater mean improvement in BASFI (-2.4 vs -0.5; p < 0.001). Through Week 16, 23.3% of patients in the PBO group and 32.4% of patients in the GOL group had ≥ 1 adverse event (AE); infections being the commonest type of AE. Through Week 28, two GOL-treated patients had a serious AE. CONCLUSION: GOL 2 mg/kg administered IV at weeks 0, 4, and every 8 weeks significantly reduced the signs and symptoms of AS in adults. AE were consistent with other antitumor necrosis factor therapies, with no new safety signals (Clinicaltrials.gov: NCT02186873).

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.

Safety and Efficacy of Intravenous Golimumab in Patients With Active Psoriatic Arthritis: Results Through Week Twenty-Four of the GO-VIBRANT Study.

OBJECTIVE: To evaluate the safety and efficacy of intravenous (IV) golimumab treatment in psoriatic arthritis (PsA). METHODS: In this phase III, randomized, double-blind, placebo-controlled trial, patients were randomly assigned to receive IV placebo (n = 239) or golimumab at 2 mg/kg (n = 241) at weeks 0, 4, 12, and 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 14. Controlled secondary end points included change from baseline in Health Assessment Questionnaire disability index (HAQ DI) score at week 14, proportions of patients with ACR50 and ACR70 responses and ≥75% improvement on the Psoriasis Area and Severity Index (a PASI75 response) at week 14, and change from baseline at week 24 in the total modified Sharp/van der Heijde score (SHS) with modifications for patients with PsA. RESULTS: At week 14, an ACR20 response was achieved by 75.1% of patients in the golimumab group compared with 21.8% of patients in the placebo group (P < 0.001). Greater proportions of golimumab-treated patients had an ACR50 response (43.6% versus 6.3%), an ACR70 response (24.5% versus 2.1%), and a PASI75 response (59.2% versus 13.6%) at week 14 (P < 0.001 for all). Patients in the golimumab group had greater mean changes at week 14 in HAQ DI score (-0.60 versus -0.12; P < 0.001). At week 24, the mean change in total PsA-modified SHS was -0.4 in the golimumab group and 2.0 in the placebo group (P < 0.001). Through week 24, 40.6% of patients in the placebo group and 46.3% of patients in the golimumab group had ≥1 adverse event (AE); infections were the most common type. CONCLUSION: Patients receiving IV golimumab at 2 mg/kg had significantly greater improvements in the signs and symptoms of PsA and less radiographic progression through week 24. AEs were consistent with those seen with other anti-tumor necrosis factor agents.

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.

OBJECTIVE: 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. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, 592 patients with active RA were randomized (2:1) to intravenous golimumab 2 mg/kg plus MTX (Group 1) or placebo plus MTX (Group 2) at weeks 0 and 4, then every 8 weeks thereafter; placebo patients crossed over to golimumab at week 16 (early escape) or week 24 (crossover). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology 20%, 50%, 70% (ACR20, ACR50, ACR70) response criteria, 28-joint count disease activity score using the C-reactive protein level (DAS28-CRP), physical function and quality of life measures, and changes in the modified Sharp/van der Heijde scores (SHS). Safety was monitored through week 112. RESULTS: In total, 486 patients (82.1%) continued treatment through week 100, and 68.1%, 43.8%, and 23.5% had an ACR20/50/70 response, respectively, at week 100. Clinical response and improvements in physical function and quality of life were generally maintained from week 24 through 2 years. Mean change from baseline to week 100 in SHS score was 0.74 in Group 1 and 2.10 in Group 2 (P = 0.005); progression from week 52 to week 100 was clinically insignificant in both groups. A total of 481 patients completed the safety followup through week 112; 79.1% had an adverse event, and 18.2% had a serious adverse event. CONCLUSION: Clinical response to IV golimumab plus MTX was maintained through week 100. Radiographic progression following golimumab treatment was clinically insignificant between week 52 and week 100. No unexpected adverse events occurred through week 112, and the safety profile was consistent with anti-tumor necrosis factor therapy.

Pharmacokinetic bridging approach for developing biologics-delivery devices: a case study with a golimumab autoinjector.

PURPOSE: This Phase 1 pharmacokinetic (PK) comparability study in healthy subjects was performed to compare the PK properties and tolerability of single-dose golimumab 100 mg delivered subcutaneously by an autoinjector device or by a standard needle and syringe that had been used for the subcutaneous (SC) delivery of golimumab in pivotal Phase 3 studies. METHODS: Healthy male subjects were randomly assigned to receive a single injection of SC golimumab 100 mg using either the autoinjector or a standard needle and syringe. The PK parameters of golimumab were calculated using noncompartmental analysis. An ANOVA model was applied to compare the 2 injection methods with regard to golimumab C(max) and the AUC from 0 and 49 days after administration (AUC(0-49d)). FINDINGS: In the prespecified evaluable PK population (n = 141), the mean (SD) values for C(max) were 6.6 (3.3) and 6.0 (3.0) µg/mL, and AUC(0-49d) values were 97.4 (43.2) and 88.9 (36.8) µg·d/mL in the autoinjector and needle/syringe groups, respectively. The 90% CI of the geometric mean ratios of the AUC(0-49d) values between the 2 delivery methods was 95.17% to 120.55%; the 90% CI of the geometric mean ratio of C(max) was 96.14% to 127.42%. In a post hoc intent-to-treat analysis using data from all 156 subjects, the 90% CIs of both C(max) and AUC(0-49d) fell within the prespecified range for bioequivalence (80% to 125%). The prevalences of adverse events were similar between the 2 groups. IMPLICATIONS: The totality of the study findings suggests that the PK properties and tolerability of SC administration of golimumab by the 2 delivery methods were comparable. The study results successfully bridged the container-closure change from a liquid-in-vial product to either a prefilled syringe or an autoinjector with the same liquid formulation.

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).

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. CLINICALTRIALSGOV: NCT00973479, EudraCT 2008-006 064-11.

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.