Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.

OBJECTIVES: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. METHODS: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. RESULTS: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. CONCLUSIONS: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. TRIAL REGISTRATION NUMBER: NCT04991753.

A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.

Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations.

OBJECTIVES: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA. METHODS: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). RESULTS: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. CONCLUSIONS: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. CLINICAL TRIAL REGISTRATION: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

Pooled safety results across phase 3 randomized trials of intravenous golimumab in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

BACKGROUND: Intravenous (IV) golimumab, a TNFi, is approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We analyzed pooled safety results from three phase 3 IV golimumab trials in these rheumatologic diseases and hypothesized that the safety profile of IV golimumab would be similar to that established for other TNFi, including subcutaneous golimumab. METHODS: Data from three double-blind, randomized trials of IV golimumab in patients with RA, PsA, and AS, each with a placebo-controlled period and an extension of active treatment, were included. Golimumab 2 mg/kg was administered at weeks 0 and 4, then every 8 weeks through week 100 (RA) or week 52 (PsA, AS). Concomitant low-dose, oral corticosteroids were permitted. Concomitant methotrexate was required in the RA trial and permitted in the PsA and AS trials; placebo patients crossed over to golimumab at weeks 24 (RA, PsA) and 16 (AS), respectively. Adverse events (AEs), including infections, serious infections, malignancies, and major adverse cardiovascular events (MACE), were assessed through week 112 (RA) or week 60 (PsA, AS). RESULTS: In total, 539 patients were randomized to placebo, and 740 patients were randomized to golimumab; 1248 patients received ≥ 1 golimumab administration. Among the placebo and golimumab patients, respectively, during the placebo-controlled periods, 40.6% and 50.3% had an AE, 2.4% and 3.8% had a serious AE, and 0.4% and 0.8% had a serious infection. Among all golimumab-treated patients, the numbers of events/100 patient-years (95% CI) were as follows: AEs, 175.2 (169.0, 181.6); serious AEs, 12.7 (11.0, 14.5); serious infections, 3.4 (2.5, 4.4); active tuberculosis, 0.4 (0.1, 0.8); opportunistic infection, 0.2 (0.1, 0.6); malignancies, 0.4 (0.2, 0.9), and MACE, 0.5 (0.2, 1.0). There were no cases of lymphoma. Three (0.6%) placebo-treated patients and 6 (0.5%) golimumab-treated patients died during the studies. Concomitant methotrexate was associated with increased occurrence of elevated alanine transaminase levels and lower incidence of antibodies to golimumab. During the placebo-controlled periods, serious infections in the placebo and golimumab groups were more common in patients receiving concomitant low-dose oral corticosteroids vs. those not receiving corticosteroids. CONCLUSIONS: IV golimumab demonstrated a safety profile that was broadly consistent across these rheumatologic indications and with other TNFi, including subcutaneous golimumab. Concomitant methotrexate or corticosteroids were associated with an increase in specific AEs. TRIAL REGISTRATIONS: ClinicalTrials.gov , NCT00973479 . Registered on September 9, 2009. CLINICALTRIALS: gov , NCT02181673 . Registered on July 4, 2014. CLINICALTRIALS: gov , NCT02186873 . Registered on July 10, 2014.

Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). METHODS: Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. RESULTS: In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. CONCLUSION: Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA.ClinicalTrials.gov number NCT02277444.

Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

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.

Three Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis.

OBJECTIVE: To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA. METHODS: In all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3. RESULTS: For study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies. CONCLUSION: In these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.

Investigation of the Mechanism of Therapeutic Protein-Drug Interaction Between Methotrexate and Golimumab, an Anti-TNFα Monoclonal Antibody.

A prominent example of human therapeutic protein-drug interaction (TP-DI) is between methotrexate (MTX) and anti-TNFα mAbs. One plausible mechanism for this TP-DI is through the pharmacodynamic effect of MTX on immunogenicity. However, there is no definitive evidence to substantiate this mechanism, and other competing hypotheses, such as MTX suppressing FcγRI expression thereby affecting mAb PK, have also been proposed. In order to understand this mechanism, a cynomolgus monkey study was conducted using golimumab as a model compound. Golimumab elicited high incidences of immunogenicity in healthy cynomolgus monkeys. Concomitant dosing of MTX delayed the onset and reduced the magnitude of anti-drug antibody (ADA) formation. The impact of MTX on golimumab PK correlated with the ADA status. Prior to ADA formation, MTX has no discernable effect on golimumab PK. Additionally, no alteration in FcγRI expression was observed following MTX treatment. The impact of MTX on golimumab immunogenicity and PK has been observed in patients with rheumatoid arthritis, psoriatic arthritis (PsA), and ankylosing spondylitis. In a representative phase 3 study of golimumab in patients with PsA, patients not receiving concomitant MTX was reported to have ~ 30% lower steady-state trough golimumab levels compared to those who received MTX. However, further analysis showed that PsA patients who were negative for ADA in both treatment groups had comparable trough levels of golimumab. Taken together, our results suggest that the mechanism of TP-DI between MTX and golimumab can mostly be attributed to the pharmacodynamic effect of MTX, i.e., the lowering of immunogenicity and immunogenicity-mediated clearance of mAbs.

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.

Safety and Efficacy of Subcutaneous Golimumab in Patients with Active Rheumatoid Arthritis despite Methotrexate Therapy: Final 5-year Results of the GO-FORWARD Trial.

OBJECTIVE: To evaluate the safety and efficacy of golimumab (GOL), a human antitumor necrosis factor antibody, in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy through 5 years in the GO-FORWARD trial. METHODS: Patients with active RA despite MTX therapy were randomly assigned to receive placebo + MTX (Group 1), GOL 100 mg + placebo (Group 2), GOL 50 mg + MTX (Group 3), or GOL 100 mg + MTX (Group 4). Patients in groups 1, 2, and 3 with inadequate response could enter early escape at Week 16 to GOL 50 mg + MTX or GOL 100 mg + MTX, and all remaining Group 1 patients crossed over to GOL 50 mg + MTX at Week 24. The blind was maintained through the 52-week database lock, after which treatment adjustments were permitted. Adverse events (AE) were monitored through Week 268. Efficacy was evaluated using the American College of Rheumatology (ACR) 20/50/70 responses and a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). Response rates at Week 256 were analyzed by an intent-to-treat analysis. RESULTS: A total of 444 patients were randomized, and 313 received GOL through Week 252; 301 patients completed the safety followup through Week 268. Infections were the most common type of AE; 172 patients (39.6%) had ≥ 1 serious AE. No unexpected safety signals were observed. At Week 256, ACR20/50/70 responses were achieved by 63.1%, 40.8%, and 24.1%, respectively, of all randomized patients. About 78% of all patients achieved a good or moderate DAS28-CRP response. CONCLUSION: Improvements in the signs and symptoms of RA were maintained through 5 years. AE through 5 years were consistent with earlier reports of the GO-FORWARD trial; no apparent increased risk was observed over time.

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.

Clinical efficacy, radiographic and safety findings through 5†years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study).

OBJECTIVES: Assess golimumab's long-term efficacy/safety in psoriatic arthritis (PsA). METHODS: Adults with active PsA (≥3 swollen and tender joints, active psoriasis) were randomly assigned to subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks (q4wks) through wk20. All patients received golimumab 50 mg or 100 mg q4wks from wk24 forward. Methotrexate was allowed and taken by approximately half the patients. Findings through 5 years are reported herein. Efficacy assessments included ≥20% improvement in American College of Rheumatology (ACR20) response, C-reactive-protein-based, 28-joint-count Disease Activity Score (DAS28-CRP) response, ≥75% improvement in Psoriasis Area and Severity Index (PASI75) scores, and PsA-modified Sharp/van der Heijde scores (SHSs). RESULTS: 126/405 (31%) randomised patients discontinued treatment through wk252. Golimumab was effective in maintaining clinical improvement through year-5 (ACR20: 62.8-69.9%, DAS28-CRP: 75.2-84.9% for randomised patients; PASI75: 60.8-72.2% among randomised patients with ≥3% body surface area involvement) and inhibiting radiographic progression (mean changes in PsA-modified SHS: 0.1-0.3) among patients with radiographic data. While concomitant methotrexate did not affect ACR20/PASI75, it appeared to reduce radiographic progression. No new safety signals were identified. Antibodies-to-golimumab occurred in 1.8%/10.0% of patients with/without methotrexate). CONCLUSIONS: Long-term golimumab safety/efficacy in PsA was demonstrated through 5 years. TRIAL REGISTRATION NUMBER: NCT00265096.