Effects of Ustekinumab on Histologic Disease Activity in Patients With Crohn's Disease.

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.

Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease.

BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. METHODS: We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. RESULTS: Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 µg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. CONCLUSIONS: In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD). METHODS: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy. RESULTS: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis. CONCLUSIONS: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and 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.

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.

The Effects of Ustekinumab on Health-related Quality of Life in Patients With Moderate to Severe Crohn's Disease.

BACKGROUND AND AIMS: We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD]. METHODS: Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re-randomised to subcutaneous maintenance therapy [IM-UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and 36-item Short Form Health Survey [SF-36] physical component summary [PCS] and mental component summary [MCS] scores were completed at induction baseline and Week 8, and at maintenance Weeks 20 and 44. Clinically meaningful improvement in IBDQ and PCS and MCS scores were evaluated. For all HRQOL outcomes, each ustekinumab dose and placebo were compared. RESULTS: Induction baseline mean values of IBDQ, PCS, and MCS were similar across groups, but impaired relative to general population norms. At Week 8, ustekinumab induced greater improvement than placebo in both HRQOL scores. Significantly greater proportions of patients receiving ustekinumab 6 mg/kg or 130 mg had clinically meaningful IBDQ improvement [UNITI-1: 54.8%, 46.9% versus 36.5%, respectively; UNITI-2: 68.1%, 58.7% versus 41.1%, respectively; p <0.05, all comparisons]. Similarly, greater proportions of ustekinumab-treated patients in both studies had clinically meaningful improvements in PCS and MCS as compared with placebo. At Week 44, improvements in IBDQ, PCS, and MCS scores were maintained with ustekinumab. CONCLUSIONS: Ustekinumab improved HRQOL in patients with moderately to severely active CD.

Premedication and infusion reactions with infliximab: results from a pediatric inflammatory bowel disease consortium.

BACKGROUND: Infusion reactions (IRs) are the most common adverse events associated with the use of infliximab for inflammatory bowel disease (IBD). Antipyretics, antihistamines, and corticosteroids have been used to prevent the development of IRs, but their efficacy is not known. We studied the proportion of pediatric patients receiving infliximab for IBD that developed IRs and the potential effects of premedication on IR. METHODS: Uniformly collected data from a cohort of pediatric patients with IBD enrolled between January 2000 and May 2003 at 6 pediatric centers were analyzed. Data were retrospectively reviewed and analyzed. RESULTS: A total of 1652 infusions given to 243 patients in 6 centers was analyzed. Overall, 60 IRs were recorded in 40 patients (3.6% of infusions, 16.5% of patients). Thirty-three of 243 patients received premedication before the first IR (group 1). Two hundred ten patients did not receive premedication until the development of IRs, if at all (group 2). IRs were more common among patients in group 1 than in group 2 (12/33 versus 28/210, P < 0.01). Of the 28 patients in group 2 with IRs, 10 began receiving premedication with each subsequent infusion, 12 continued without premedications, and 6 had no further infusions recorded. Two of 10 who began receiving premedication had a subsequent IR versus 6 of 12 who did not receive premedication (P = 0.15). CONCLUSIONS: IRs occur in a small proportion of infusions among pediatric patients receiving infliximab for IBD. Premedication does not seem to prevent the development of IRs; however, once an IR has occurred, premedication may be indicated to prevent subsequent IRs.

Retention of Endogenous Viable Cells Enhances the Anti-Inflammatory Activity of Cryopreserved Amnion.

Objective: Human amniotic membrane (hAM) has been used to treat wounds for more than 100 years. However, widespread use of fresh hAM has been limited due to its short shelf life and safety concerns. To overcome these concerns, different preservation methods have been introduced. The majority of these methods result in devitalized hAM (dev-hAM). Recently, we developed a cryopreservation method that retains all hAM components intact (int-hAM), including viable endogenous cells. To understand the advantages of retaining viable cells in preserved hAM, we compared the anti-inflammatory properties of int-hAM and dev-hAM. Approach: The tissue composition of int-hAM and dev-hAM was compared with fresh hAM through histology and cell viability analysis. We also evaluated the ability of int-hAM and dev-hAM to regulate tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and IL-10 release when co-cultured with immune cells; to produce prostaglandin E2 (PGE2) on TNF-α stimulation; and to inhibit proteases. Results: Int-hAM maintained the structural and cellular integrity of fresh hAM. Int-hAM had >80% cell viability post-thaw and remained viable for at least a week in culture. Viable cells were not detected in dev-hAM. Compared with dev-hAM, int-hAM showed significantly greater downregulation of TNF-α and IL-1α, upregulation of PGE2 and IL-10, and stronger inhibition of collagenase. Innovation and Conclusion: A new cryopreservation method has been developed to retain all native components of hAM. For the first time, we show that viable endogenous cells significantly augment the anti-inflammatory activity of cryopreserved hAM.

Soluble Factors Released by Endogenous Viable Cells Enhance the Antioxidant and Chemoattractive Activities of Cryopreserved Amniotic Membrane.

Objective: Regulation of oxidative stress and recruitment of key cell types are activities of human amniotic membrane (hAM) that contribute to its benefits for wound treatment. Progress in tissue preservation has led to commercialization of hAM. The majority of hAM products are devitalized with various degrees of matrix alteration. Data show the importance of hAM matrix preservation, but little is known about the advantages of retaining viable endogenous cells. In this study, we compared the antioxidant and chemoattractive properties of viable intact cryopreserved hAM (int-hAM) and devitalized cryopreserved hAM (dev-hAM) to determine the benefits of cell preservation. Approach: We evaluated the ability of int-hAM and dev-hAM to protect fibroblasts from oxidant-induced cell damage, to suppress oxidants, and to recruit fibroblasts and keratinocytes in vitro. Results: Both the int-hAM-derived conditioned medium (CM) and the int-hAM tissue rescued significantly more fibroblasts from oxidant-induced damage than dev-hAM (844% and 93% more, respectively). The int-hAM CM showed a 202% greater antioxidant capacity than dev-hAM. The int-hAM CM enhanced the recruitment of fibroblasts and normal and diseased keratinocytes to a greater extent than dev-hAM (1,555%, 315%, and 151% greater, respectively). Innovation and Conclusion: Int-hAM, in which all native components are preserved, including endogenous viable cells, demonstrated a significantly greater antioxidant and fibroblast and keratinocyte chemoattractive potential compared to dev-hAM, in which viable cells are destroyed. The release of soluble factors that protect fibroblasts from oxidative injury by hAM containing viable cells is a mechanism of hAM antioxidant activity, which is a novel finding of this study.

A retrospective analysis of a human cellular repair matrix for the treatment of chronic wounds.

Despite the introduction of advanced wound care modalities over the last 15 years, chronic wounds are an increasing problem. Few single options are available for clinicians to treat recalcitrant wounds such as diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs). A retrospective, single-center study was conducted at an outpatient wound care center to evaluate the clinical effect of a human cellular repair matrix (h-CRM) on chronic wounds that had failed to heal. Data from all patients who had received this treatment modality during a period of 2 years were abstracted. Standard care included weekly visits, regular debridement, offloading DFUs, compression for VLUs, and h-CRM for wounds >4 weeks duration. A total of 66 patients (30 male, 36 female, mean age 71.1 [± 8.8] years) received h-CRM treatment for 67 wounds (34 VLUs, 27 DFUs, and six other chronic wounds). The average wound size at baseline was 6.65 (± 9.68) cm2, and the average wound duration before h-CRM treatment was 38 (±70.8) weeks. Fifty (50) patients (74.6%) had failed to heal using other advanced therapies. After 12 weeks of care, 51 of the 67 wounds (76.1%) were healed: 23 of 34 (67.6%) VLUs and 23 of 27 (85.2%) DFUs. Average time to closure in these wounds was 5.8 (±2.5) weeks. No significant differences were found between proportions of VLUs and DFUs healed. No adverse events or recurrences occurred during an average follow-up time of 20.4 months (range 11 to 32 months). Overall, patients received an average of 3.8 applications of h-CRM, and 3.2 applications were used among patients that healed. The study results suggest h-CRM may benefit patients with chronic wounds. Prospective, randomized clinical studies are warranted.

Predictors of immunomodulator use as early therapy in pediatric Crohn's disease.

GOALS: The goals of this study were to identify markers in a patient's presentation and disease progression that predict the need for the use of immunomodulators in a pediatric population. BACKGROUND: Although immunomodulator safety and efficacy have been documented in Crohn's disease, models for predicting outcome and the need for immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) early in the disease course have not been investigated in children or adults. METHODS: Data on newly diagnosed Crohn's disease patients were prospectively collected within 3 weeks of diagnosis, 6 months after diagnosis, and 1 year after diagnosis. Information collected at each visit included medication use and disease activity assessment. RESULTS: A total of 57 patients who were followed for > or = 6 months were evaluated. Overall, 34 of 57 (59.6%) were started on immunomodulators within 1 year of diagnosis. Mean serum albumin (3.35 g/dL vs. 3.7 g/dL, P = 0.013) and hematocrit (33.3% vs. 35.9%, P = 0.023) at diagnosis were lower, and erythrocyte sedimentation rate (32 vs. 12, P = 0.011) at diagnosis was higher in patients who required immunomodulators. The total Pediatric Crohn's Disease Activity Index score as well as the physical examination score and patient recall score within the PCDAI at diagnosis were not different among those who received immunomodulators and those that did not. CONCLUSIONS: Immunomodulators are frequently used within 1 year of diagnosis in pediatric Crohn's disease. Lower serum albumin levels and hematocrit, and elevated erythrocyte sedimentation rate at diagnosis may predict the need for immunomodulators earlier in the disease course.