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.

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. METHODS: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. RESULTS: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44. CONCLUSIONS: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8. CLINICALTRIALS: gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Population Pharmacokinetics and Exposure-Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease.

PURPOSE: Ustekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure-response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies. METHODS: Serum ustekinumab concentration-time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n = 1910) and maintenance (n = 387) treatment. FINDINGS: Ustekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t1/2 was 19 days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values. IMPLICATIONS: In patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ∼6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. CLINICALTRIALS: gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study.

BACKGROUND & AIMS: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy. METHODS: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. RESULTS: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: -160.4, 600 mg: -138.9, and 1200 mg: -144.9 vs placebo: -36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn's Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups. CONCLUSIONS: At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. CLINICALTRIALS: gov, Number: NCT03466411.

Population Pharmacokinetic and Exposure-Response Model Simulations: Predicted Exposure and Efficacy for Maintenance Doses of Intravenous Golimumab Every 6 or 8 Weeks in Patients With Moderately to Severely Active Rheumatoid Arthritis.

PURPOSE: Golimumab is approved to treat moderate-to-severe active rheumatoid arthritis when given intravenously at weeks 0 and 4, then every 8 weeks (Q8W) with concomitant methotrexate. These analyses assessed whether a shorter dosing interval could ameliorate diminished efficacy experienced by a small proportion of patients toward the end of the dosing interval. METHODS: Population pharmacokinetic and exposure-response modeling simulations were performed for intravenous golimumab 2 mg/kg at weeks 0 and 4, then Q8W or every 6 weeks (Q6W) through 1 year. A 2-compartment pharmacokinetic model with linear clearance developed based on GO-FURTHER (A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFα Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy) study data was used for pharmacokinetic simulations. A latent-variable indirect exposure-response model developed based on GO-FURTHER American College of Rheumatology (ACR) 20%/50%/70% improvement (ACR20, ACR50, and ACR70, respectively) data was used to predict clinical endpoints of ACR20/ACR50/ACR70 response rates. FINDINGS: For Q6W and Q8W dosing, respectively, predicted median golimumab steady-state trough (Ctrough,ss) concentrations were 0.57 and 0.24 µg/mL, and Cmax at steady state values were 33.1 and 32.9 µg/mL. Predicted peak median ACR20 steady-state response rates were 76.7% (Q6W) and 75.6% (Q8W). Predicted median ACR20 response rates at Ctrough,ss increased by 4.7 percentage points with Q6W (73.7%) versus Q8W (69.0%) dosing. Greater improvement in ACR20 response rates at trough time points was predicted in patients with lower golimumab trough serum concentrations. Consistent findings were observed for ACR50/ACR70 response rates. IMPLICATIONS: These simulations suggest that intravenous golimumab Q6W dosing increases golimumab Ctrough,ss, which may improve clinical response in the small proportion of patients with rheumatoid arthritis with waning efficacy at the end of the standard dosing interval. CLINICALTRIALS: gov identifier: NCT00973479. Clinicaltrialsregister.eu: EudraCT 2008-006064-11.

Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial.

BACKGROUND & AIMS: The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years. METHODS: Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively. RESULTS: Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE. CONCLUSIONS: Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn's Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study.

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.

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

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).

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Ustekinumab in Adults With Moderately to Severely Active Ulcerative Colitis.

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.

Population Pharmacokinetics and Exposure-Response Modeling of Golimumab in Adults With Moderately to Severely Active Ulcerative Colitis.

PURPOSE: Golimumab is a fully human monoclonal antibody to tumor necrosis factor-α and is indicated for the treatment of moderately to severely active ulcerative colitis (UC). This study analyzed the population pharmacokinetic (PK) properties of golimumab and exposure-response for efficacy and safety, using data from combined Phase II/III UC studies. METHODS: Data on serum golimumab concentration following IV and subcutaneous (SC) administration were fitted simultaneously using nonlinear mixed-effects modeling for the development of a population PK model. Logistic regression models were used for assessing relationships between serum golimumab concentrations and clinical efficacy outcomes in SC induction and maintenance studies. The percentages of patients developing infections, serious infections, and serious adverse events were assessed by golimumab exposure metric quartiles. FINDINGS: The PK properties of golimumab are well described by a 2-compartment model with first-order absorption and elimination. Typical values of PK parameters in a 70-kg patient were clearance, 0.544 L/d; central and peripheral compartment Vd, 3.43 and 2.27 L, respectively; and intercompartmental clearance, 0.291 L/d. Golimumab t1/2 was 10.5 days; bioavailability following SC administration was 52.2%. Body weight, anti-golimumab antibodies, serum albumin, C-reactive protein, and alkaline phosphatase affected golimumab disposition. A positive exposure-response relationship was established between golimumab concentration and efficacy outcomes. No apparent correlation between golimumab exposure and rate of infections, serious infections, or serious adverse events was observed in patients receiving golimumab 50 or 100 mg SC every 4 weeks through 1 year. IMPLICATIONS: Body weight, serum albumin, and anti-golimumab antibodies explain some of the variability observed in the PK properties of golimumab, and exposure-response findings support the recommended posology of golimumab in UC. ClinicalTrials.gov identifiers: NCT00488774, NCT00487539, and NCT00488631.

Maintenance Golimumab Treatment in Pediatric UC Patients With Moderately to Severely Active UC: PURSUIT PEDS PK Long-Term Study Results.

Background: Long-term safety, pharmacokinetics, and efficacy of open-label golimumab therapy in children with moderate-severe ulcerative colitis were evaluated. Methods: Week-6 golimumab responders (Mayo score decrease of ≥30% and ≥3 points from baseline, rectal bleeding subscore of 0/1 or ≥1 decrease from baseline) entered the long-term extension at week 14 and received maintenance therapy (subcutaneous, q4w). Patients ≥45 kg could receive at-home treatments at week 18. Pharmacokinetic, safety, and efficacy results were summarized through week 126 (2 years). Results: Among 35 enrolled children, 21 (60%) responded at week 6 and 20 entered the long-term extension (median age of 14.5 years and median weight of 46.1 kg). Eleven of 20 patients (55%) completed 2 years of treatment. No anaphylactic or serum sickness-like reactions, opportunistic infections, malignancies, tuberculosis, or deaths occurred. The safety profile of golimumab from weeks 14 through 126 and that observed through week 14 was generally consistent. Median trough golimumab concentrations in evaluable patients were consistent from weeks 14 (1.39, interquartile range 0.67-3.60) through 102 (1.18, 0.78-2.16), but higher at week 110 (4.10, 1.30-4.81). The incidence of antigolimumab antibodies increased from 10% (2/20) at week 30 to 25.0% (5/20) at week 126; 1 patient had neutralizing antibodies. At week 110, 50% (10/20) of patients were in remission (ie, Pediatric Ulcerative Colitis Activity Index <10). Among all enrolled patients, 28.6% (10/35) achieved remission at week 110. Conclusions: Among children with ulcerative colitis who initially responded to golimumab induction and received q4w maintenance treatment in the long-term extension, 50% showed continued clinical benefit through 2 years. No new safety signals were observed.

IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn's Disease.

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.

Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. METHODS: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. RESULTS: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 µg/mL. A steady-state trough serum concentration of 1.3 µg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. CONCLUSIONS: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Immunogenicity of Golimumab and its Clinical Relevance in Patients With Ulcerative Colitis.

BACKGROUND: Antidrug antibody (ADA) detection with standard bridging enzyme immunoassays (EIA) can yield false-negative results or underestimate titers through drug interference. A more sensitive assay was needed to determine clinical impact of antigolimumab antibodies. METHODS: A high-sensitivity, drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original EIA, and samples from induction/maintenance studies in golimumab-treated patients with ulcerative colitis were analyzed for ADAs using both methods. Immunogenicity results were compared, and pharmacokinetic, efficacy, and safety associations were evaluated. RESULTS: An 8-fold increase in ADA-positive patients (21.8% DT-EIA vs 2.8% EIA) reflected DT-EIA improved sensitivity and drug tolerance. Most newly detected ADA-positive patients (using DT-EIA) had low antibody titers, whereas most with high antibody titers were ADA-positive with original EIA. With DT-EIA, week 44 median trough serum golimumab concentrations among ADA-positive patients were approximately half vs ADA-negative (0.51 vs 0.85 µg/mL [50 mg q4w]; 0.85 vs 1.60 µg/mL [100 mg q4w]). Antidrug antibody impact on golimumab concentrations was more notable at titers ≥1:100. During induction, ADAs had no notable impact on efficacy. During maintenance, proportions of patients maintaining clinical response through week 54 were lower using DT-EIA: 38.1% ADA-positive and 52.8% ADA-negative. Antidrug antibody status had no impact on injection-site reaction incidence. CONCLUSIONS: A more sensitive DT-EIA identified higher proportions of ADA-positive patients. A trend of decreasing drug concentrations with increasing ADA titers was observed. Pharmacokinetic impact was better elucidated with DT-EIA. Although development of ADA did not preclude efficacy, a trend toward decreased efficacy in ADA-positive vs ADA-negative patients was observed during maintenance treatment. Antidrug antibody status did not impact safety.

Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis.

BACKGROUND & AIMS: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. METHODS: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared. RESULTS: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. CONCLUSION: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.

Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

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.

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis.

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.

Modeling near-continuous clinical endpoint as categorical: application to longitudinal exposure-response modeling of Mayo scores for golimumab in patients with ulcerative colitis.

Accurate characterization of exposure-response relationship of clinical endpoints is important in drug development to identify optimal dose regimens. Endpoints with ≥ 10 ordered categories are typically analyzed as continuous. This manuscript aims to show circumstances where it is advantageous to analyze such data as ordered categorical. The results of continuous and categorical analyses are compared in a latent-variable based Indirect Response modeling framework for the longitudinal modeling of Mayo scores, ranging from 0 to 12, which is commonly used as a composite endpoint to measure the severity of ulcerative colitis (UC). Exposure response modeling of Mayo scores is complicated by the fact that studies typically include induction and maintenance phases with re-randomizations and other response-driven dose adjustments. The challenges are illustrated in this work by analyzing data collected from 3 phase II/III trials of golimumab in patients with moderate-to-severe UC. Visual predictive check was used for model evaluations. The ordered categorical approach is shown to be accurate and robust compared to the continuous approach. In addition, a disease progression model with an empirical bi-phasic rate of onset was found to be superior to the commonly used placebo model with one onset rate. An application of this modeling approach in guiding potential dose-adjustment was illustrated.

Long-Term Benefit of Golimumab for Patients with Moderately to Severely Active Ulcerative Colitis: Results from the PURSUIT-Maintenance Extension.

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.