In two trials in patients with moderately to severely active Crohn's disease, intravenous ustekinumab was effective in those who did not have a response to conventional therapy or TNF antagonists. ...Subcutaneous ustekinumab was more effective than placebo in maintaining remission.
Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that is treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists, or integrin inhibitors.
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The drawbacks of these agents include an increased risk of infection
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and cancer
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and limited efficacy.
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Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 that has been approved for use in the treatment of psoriasis and psoriatic arthritis.
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In previous trials involving patients with psoriasis in which ustekinumab was administered subcutaneously for up to 5 years, the drug was not associated with an increased risk of serious adverse . . .
Patients with moderate-to-severe ulcerative colitis were randomly assigned to receive placebo or induction doses of ustekinumab. Patients who had a response to induction therapy underwent a second ...randomization to maintenance therapy with ustekinumab or placebo. Ustekinumab was more effective than placebo for inducing and maintaining remission.
Background Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate-to-severe plaque psoriasis. Objective ...To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods Analysis of 52-week data from CLEAR, a randomized, double-blind, phase 3b study. Results Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% P < .0001); PASI 100 responses were 46% versus 36% ( P = .0103) and Investigator's Global Assessment responses of clear/almost clear skin were 80% versus 65% ( P < .0001). Subjects on secukinumab reported greater reductions in psoriasis-related pain, itching, and scaling, and greater improvement across all quality-of-life measures evaluated (Dermatology Life Quality Index DLQI, EuroQoL 5-Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire-Psoriasis, and Health Assessment Questionnaire-Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab ( P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations There was no placebo arm. Conclusion In this head-to-head, double-blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.
The treatment of hidradenitis suppurativa (HS) has remained challenging because of the many knowledge gaps regarding etiology. However, recent studies into the pathogenesis of HS have enabled the ...investigation of newer therapies. The second article in this continuing medical education series reviews the evidence for established therapies for HS, including anti-inflammatories, antibiotics, and surgery. New and emerging therapies that specifically target cytokines involved in HS pathogenesis will be covered. The potential therapeutic roles of anticytokine therapies, including both the expanded application of existing molecules as well as the specific development of novel therapies for HS are discussed. With increased attention on HS and with numerous clinical trials currently underway, we hope that the variety of treatment options for HS will be expanded.
Abstract
Background
Ustekinumab is currently approved globally in Crohn’s disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn’s ...disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses.
Methods
Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed.
Results
Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 95% CI, 155.81–176.67 vs ustekinumab 118.32 95% CI, 113.25–123.55), serious AEs (27.50 95% CI, 23.45–32.04 vs 21.23 95% CI, 19.12–23.51), infections (80.31 95% CI, 73.28–87.84 vs 64.32 95% CI, 60.60–68.21), serious infections (5.53 95% CI, 3.81–7.77 vs 5.02 95% CI, 4.02–6.19), and malignancies excluding nonmelanoma skin cancer (0.17 95% CI, 0.00–0.93 vs 0.40 95% CI, 0.16–0.83) were similar between placebo and ustekinumab.
Conclusions
The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications.
ClinicalTrials.gov numbers
NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.
Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). ...This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice.
Consecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up.
One hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal.
Subcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.
Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA). The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and ...guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy.
Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week). The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28. Safety was monitored through week 48.
At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups. Infections were the most common type of AE.
Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA. No new safety findings were observed with either treatment.
NCT01645280.
Risankizumab is a humanised IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23, inhibiting this key cytokine and its role in psoriatic inflammation. We aimed to assess the ...efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis.
UltIMMa-1 and UltIMMa-2 were replicate phase 3, randomised, double-blind, placebo-controlled and active comparator-controlled trials done at 139 sites in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain, and the USA. Eligible patients were 18 years or older, with moderate-to-severe chronic plaque psoriasis. In each study, patients were stratified by weight and previous exposure to tumour necrosis factor inhibitor and randomly assigned (3:1:1) by use of interactive response technology to receive 150 mg risankizumab, 45 mg or 90 mg ustekinumab (weight-based per label), or placebo. Following the 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16–52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B. Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16 (non-responder imputation). All efficacy analyses were done in the intention-to-treat population. These trials are registered with ClinicalTrials.gov, numbers NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2), and have been completed.
Between Feb 24, 2016, and Aug 31, 2016, 506 patients in UltIMMa-1 were randomly assigned to receive 150 mg risankizumab (n=304), 45 mg or 90 mg ustekinumab (n=100), or placebo (n=102). Between March 1, 2016, and Aug 30, 2016, 491 patients in UltIMMa-2 were randomly assigned to receive 150 mg risankizumab (n=294), 45 mg or 90 mg ustekinumab (n=99), or placebo (n=98). Co-primary endpoints were met for both studies. At week 16 of UltIMMa-1, PASI 90 was achieved by 229 (75·3%) patients receiving risankizumab versus five (4·9%) receiving placebo (placebo-adjusted difference 70·3% 95% CI 64·0–76·7) and 42 (42·0%) receiving ustekinumab (ustekinumab-adjusted difference 33·5% 22·7–44·3; p<0·0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74·8%) patients receiving risankizumab versus two (2·0%) receiving placebo (placebo-adjusted difference 72·5% 95% CI 66·8–78·2) and 47 (47·5%) receiving ustekinumab (ustekinumab-adjusted difference 27·6% 16·7–38·5; p<0·0001 vs placebo and ustekinumab). In UltIMMa-1, sPGA 0 or 1 at week 16 was achieved by 267 (87·8%) patients receiving risankizumab versus eight (7·8%) receiving placebo (placebo-adjusted difference 79·9% 95% CI 73·5–86·3) and 63 (63·0%) receiving ustekinumab (ustekinumab-adjusted difference 25·1% 15·2–35·0; p<0·0001 vs placebo and ustekinumab). In UltIMMa-2, 246 (83·7%) patients receiving risankizumab versus five (5·1%) receiving placebo (placebo-adjusted difference 78·5% 95% CI 72·4–84·5) and 61 (61·6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab-adjusted difference 22·3% 12·0–32·5; p<0·0001 vs placebo and ustekinumab). The frequency of treatment-emergent adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab (part A: 151 49·7% of 304 and 134 45·6% of 294; part B: 182 61·3% of 297 and 162 55·7% of 291), placebo (part A: 52 51·0% of 102 and 45 45·9% of 98), ustekinumab (part A: 50 50·0% of 100 and 53 53·5% of 99; part B: 66 66·7% of 99 and 70 74·5% of 94), and placebo to risankizumab (part B: 65 67·0% of 97 and 61 64·9% of 94) treatment groups throughout the study duration.
Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis. Treatment-emergent adverse event profiles were similar across treatment groups and there were no unexpected safety findings.
AbbVie and Boehringer Ingelheim.
Background Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has shown superior efficacy to etanercept with similar safety in moderate to severe plaque psoriasis (FIXTURE study). ...Objective We sought to directly compare efficacy and safety of secukinumab versus ustekinumab. Methods In this 52-week, double-blind study ( NCT02074982 ), 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label. Primary end point was 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI) score (PASI 90) at week 16. Results Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90 response at week 16 ( P < .0001). The 100% improvement from baseline PASI score at week 16 was also significantly greater with secukinumab (44.3%) than ustekinumab (28.4%) ( P < .0001). The 75% or more improvement from baseline PASI score at week 4 was superior for secukinumab (50.0%) versus ustekinumab (20.6%) ( P < .0001). Percentage of subjects with the Dermatology Life Quality Index score 0/1 (week 16) was significantly higher with secukinumab (71.9%) than ustekinumab (57.4%) ( P < .0001). The safety profile of secukinumab was comparable with ustekinumab and consistent with pivotal phase III secukinumab studies. Limitations The study was not placebo-controlled and of short-term duration. Conclusions Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe psoriasis and improving health-related quality of life with a comparable safety profile over 16 weeks.
Abstract
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.
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