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Background and Aims The objective was to evaluate the pharmacokinetics, safety/tolerability, and efficacy of ustekinumab in children with moderately to severely active Crohn's disease. Methods In this Phase 1, multicentre, 16-week, double-blind, induction dose-ranging study [NCT02968108], patients aged 2‐<18 years [body weight ≥10 kg] were randomised [1:1] to one of two weight range-based intravenous induction doses: 130 mg vs 390 mg in patients ≥40kg and 3 mg/kg vs 9 mg/kg in patients <40kg. At Week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90 mg in patients ≥40kg or 2 mg/kg in patients <40kg. Results A total of 44 patients were randomised and treated with ustekinumab [ n = 23 lower dose; n = 21 higher dose]; median [interquartile range] age was 13.0 [12–16] years. Pharmacokinetics were similar to those in adults with Crohn's disease. However, serum ustekinumab concentrations were lower among those with body weight <40 kg compared with patients ≥40 kg and the reference Phase 3 adult population. Through Week 16, 73% of patients reported ≥1 adverse event [82.6% lower vs 62% higher dose]; two discontinued due to adverse events [one in each group]. Serious adverse events occurred in 16% [26% lower, 5% higher dose], with Crohn's disease exacerbation being the most frequent. At Week 16, 22%/29% [lower/higher dose] achieved clinical remission [Paediatric Crohn's Disease Activity Index ≤10]. Conclusions The pharmacokinetics/safety profiles were generally consistent with those observed in adults with Crohn's disease. These results suggest a different dosing regimen may be required for patients <40 kg from that employed in this study; additional pharmacokinetic analyses may be needed in this population. [ABSTRACT FROM AUTHOR]

Summary: Background: The ongoing UNIFI long‐term extension evaluates subcutaneous ustekinumab for moderate‐to‐severe ulcerative colitis (UC) from weeks 44 through 220. Aims: To assess efficacy (through week 92) and safety (through week 96) during the long‐term extension Methods: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long‐term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. Results: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long‐term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid‐free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient‐years (PY) of follow‐up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non‐melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. Conclusions: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236). [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetics (PK) and exposure‐response (E‐R) relationship of ustekinumab, an anti‐interleukin‐12/interleukin‐23 (IL‐12/IL‐23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E‐R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration‐time data of ustekinumab were adequately described by a 2‐compartment linear PK model with first‐order absorption and first‐order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E‐R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E‐R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90‐mg subcutaneous every‐8‐week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90‐mg subcutaneous every‐12‐week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E‐R in a modeling framework to support ustekinumab dose recommendations in patients with UC. [ABSTRACT FROM AUTHOR]

Background and Aims Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported. Methods At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits. Results Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0–152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]. Conclusions Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics (PK) and exposure‐response (E‐R) analyses were conducted to compare the PK and E‐R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6‐17 years) in the PURSUIT‐PEDS‐PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2‐17 years) in the GO‐KIDS study, were included in the population PK analysis. E‐R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score–based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1‐compartment model with first‐order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model‐estimated terminal half‐life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT‐PEDS‐PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E‐R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E‐R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population. [ABSTRACT FROM AUTHOR]

Objective Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. Methods A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. Results The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. Conclusion ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. Trial registration NCT00264550, NCT00265096, NCT00265083. [ABSTRACT FROM AUTHOR]

Background and Aims To evaluate the safety and efficacy of 3 additional years of subcutaneous golimumab maintenance in patients with moderately to severely active ulcerative colitis. Methods The PURSUIT-maintenance long-term extension enrolled patients who had completed placebo or golimumab 50 mg or 100 mg treatment every 4 weeks [q4w] through Week 52 and evaluations at Week 54 [ n = 666]; treatment continued through Week 212. Patients receiving placebo were discontinued after study unblinding. Efficacy endpoints, golimumab concentrations, and anti-drug antibodies were summarized as observed for golimumab-induction responders who continued golimumab therapy during the long-term extension. Observations relating to safety were summarized for all treated patients. Results Overall, 63% of patients who were receiving golimumab at the beginning of the extension remained on treatment through the end of the study. Among all treated patients in the extension, rates of adverse events of special interest [e.g. tuberculosis, demyelination, and malignancy] were infrequent. Nine deaths occurred during the extension [1 placebo, 1 golimumab 50 mg, and 7 golimumab 100 mg]. Serum golimumab concentrations were dose-proportional and were maintained over time. During the extension through Week 228, anti-drug antibody rates with golimumab 50 mg and 100 mg were 4.4% and 3.7%, respectively. Among golimumab-induction responders, 99.3% had no disease or mild disease activity as per the Physician’s Global Assessment, 92.5% were corticosteroid-free, and 76.1% had an Inflammatory Bowel Disease Questionnaire score of ≥170 at Week 216. Conclusions Subcutaneous golimumab treatment of moderately to severely active ulcerative colitis for up to 3 additional years during the extension maintained clinical benefit with no new safety signals observed. ClinicalTrials.gov number NCT00488631. [ABSTRACT FROM AUTHOR]

Background: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.Objective: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.Methods: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers.Results: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected.Conclusions: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated. [ABSTRACT FROM AUTHOR]

Background & Aims: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) −α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF−α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. Methods: We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6−12; endoscopic subscore ≥2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. Results: In phase 2, median changes from baseline in the Mayo score were −1.0, −3.0, −2.0, and −3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess. Conclusions: Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539. [Copyright &y& Elsevier]