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Philippe Szapary - One of the best experts on this subject based on the ideXlab platform.
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Ustekinumab pharmacokinetics and exposure response in a phase 3 randomized trial of patients with ulcerative colitis
Clinical Gastroenterology and Hepatology, 2020Co-Authors: Omoniyi J Adedokun, Jewel Johanns, Philippe Szapary, C D Obrien, Colleen Marano, Hongyan Zhang, Gert Van Assche, Rupert W Leong, Tadakazu Hisamatsu, Silvio DaneseAbstract: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.
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efficacy of Ustekinumab for inducing endoscopic healing in patients with crohn s disease
Gastroenterology, 2018Co-Authors: Paul Rutgeerts, Christopher Gasink, Jewel Johanns, Douglas Jacobstein, Daphne Chan, Yinghua Lang, Paul F. Pollack, Jean-frederic Colombel, Douglas C. Wolf, Philippe SzaparyAbstract: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).
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Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn’s Disease
Gastroenterology, 2018Co-Authors: Paul Rutgeerts, Christopher Gasink, Jewel Johanns, Douglas Jacobstein, Daphne Chan, Yinghua Lang, Paul F. Pollack, Jean-frederic Colombel, Douglas C. Wolf, Philippe SzaparyAbstract: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).
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Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease.
Gastroenterology, 2018Co-Authors: Omoniyi J Adedokun, Christopher Gasink, Long Long Gao, Jewel Johanns, Stephen B Hanauer, Philippe Szapary, Douglas Jacobstein, Hugh M. Davis, Brian G FeaganAbstract: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).
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the safety of Ustekinumab treatment in patients with moderate to severe psoriasis and latent tuberculosis infection
British Journal of Dermatology, 2012Co-Authors: Tsen-fang Tsai, Craig L Leonardi, Philippe Szapary, Michael Song, T Kato, Y Wasfi, Yaungkaung Shen, Japanese Ustekinumab Study GroupsAbstract:Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12/23 p40 to treat psoriasis. The IL-12 pathway is also important in regulating immunity to Mycobacterium tuberculosis. Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in Ustekinumab-treated patients with psoriasis. Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of Ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON®-TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis. Results At baseline, 101/2898 (3·5%) non-Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and Ustekinumab-treated patients, as well as between Ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and Ustekinumab-treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and Ustekinumab groups through week 12. The rate of INH-related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline. Conclusions Across five trials of Ustekinumab-treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.
Cynthia Guzzo - One of the best experts on this subject based on the ideXlab platform.
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Ustekinumab induction and maintenance therapy in refractory crohn s disease
The New England Journal of Medicine, 2012Co-Authors: William J Sandborn, Cynthia Guzzo, Bruce E. Sands, Christopher Gasink, Long Long Gao, Marion Blank, Jewel Johanns, Stephen B Hanauer, Stephan R Targan, Paul RutgeertsAbstract:A b s t r ac t The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of Ustekinumab per kilogram, respectively, as com- pared with 23.5% for placebo (P = 0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with Ustekinumab, as com- pared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P = 0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving Ustekinumab) during induction and 11 patients (4 receiving Ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving Ustekinumab. Conclusions Patients with moderate-to-severe Crohn's disease that was resistant to TNF antago - nists had an increased rate of response to induction with Ustekinumab, as compared with placebo. Patients with an initial response to Ustekinumab had significantly increased rates of response and remission with Ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov num- ber, NCT00771667.)
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long term safety experience of Ustekinumab in patients with moderate to severe psoriasis part i of ii results from analyses of general safety parameters from pooled phase 2 and 3 clinical trials
Journal of The American Academy of Dermatology, 2012Co-Authors: Mark Lebwohl, Newman Yeilding, Cynthia Guzzo, Christopher E M Griffiths, Craig L Leonardi, J C Prinz, Philippe Szapary, Ming Chun Hsu, Bruce E StroberAbstract:Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. Objective To evaluate overall pooled study data to assess the safety profile of Ustekinumab through 3 years of treatment. Methods Cumulative safety data were pooled from studies in 3117 Ustekinumab-treated patients. Results During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with Ustekinumab 45 mg (57.6%), or with Ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; Ustekinumab 45 mg: 66.0%; and Ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between Ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. Limitations Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 Ustekinumab-treated patients were treated for 2 or more years. Conclusions The safety profile of continued Ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.
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long term safety experience of Ustekinumab in patients with moderate to severe psoriasis part ii of ii results from analyses of infections and malignancy from pooled phase ii and iii clinical trials
Journal of The American Academy of Dermatology, 2012Co-Authors: Kenneth B. Gordon, Newman Yeilding, Cynthia Guzzo, Kim Papp, Richard G Langley, Philippe Szapary, Ming Chun Hsu, Alexa B Kimball, Steven Fakharzadeh, Kristian ReichAbstract:Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. Objective We sought to evaluate the impact of Ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. Methods Rates of infections and malignancies were evaluated in cumulative safety data from 3117 Ustekinumab-treated patients across 4 studies. Results During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), Ustekinumab 45-mg (145.7), and Ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in Ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in Ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. Limitations Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. Conclusions The emerging safety profile of Ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.
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efficacy and safety of Ustekinumab for the treatment of moderate to severe psoriasis a phase iii randomized placebo controlled trial in taiwanese and korean patients pearl
Journal of Dermatological Science, 2011Co-Authors: Tsen-fang Tsai, Cynthia Guzzo, Philippe Szapary, Michael Song, Yuangkuang Shen, Kwangjoong Kim, Taeyoon Kim, Jee Ho Choi, J I YounAbstract:Abstract Background Ustekinumab has been evaluated in Caucasian patients with psoriasis, but no studies have been conducted in Asian patients. Objective To assess the efficacy and safety of Ustekinumab in Taiwanese and Korean patients with moderate-to-severe psoriasis. Methods In this 36-week, multicenter, double-blind, placebo-controlled study, 121 patients with moderate-to-severe psoriasis were randomized (1:1) to receive subcutaneous injections of Ustekinumab 45 mg at weeks 0, 4, 16 or placebo at weeks 0, 4 and Ustekinumab 45 mg at weeks 12, 16. Efficacy endpoints at week 12 included the proportion of patients achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75; primary endpoint), proportion of patients with Physician's Global Assessment (PGA) of cleared or minimal, and change from baseline in Dermatology Life Quality Index (DLQI). Results At week 12, the proportion of patients achieving PASI 75 was 67.2% and 5.0% in the Ustekinumab 45 mg and placebo groups, respectively (p Conclusions Treatment with subcutaneous Ustekinumab 45 mg offers a favorable benefit/risk profile for Taiwanese and Korean patients with moderate-to-severe psoriasis. The efficacy and safety profile is consistent with the global phase III studies of Ustekinumab in psoriasis.
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cardiovascular safety of Ustekinumab in patients with moderate to severe psoriasis results of integrated analyses of data from phase ii and iii clinical studies
British Journal of Dermatology, 2011Co-Authors: Kristian Reich, Newman Yeilding, Cynthia Guzzo, Mark Lebwohl, Philippe Szapary, Ming Chun Hsu, R G Langley, Christopher E M GriffithsAbstract:BACKGROUND: Patients with psoriasis are believed to be at an increased risk of cardiovascular (CV) morbidity, and the effect of biological agents on CV safety is not fully understood. OBJECTIVES: To evaluate the effect of Ustekinumab on CV events using detailed analyses of pooled data from the phase II/III clinical studies of its use in moderate to severe psoriasis. METHODS: The incidence of major adverse CV events [MACE: myocardial infarction (MI), stroke or CV death] is reported. Meta-analyses using risk difference and odds ratio estimates are presented based on data collected during the placebo-controlled period of Ustekinumab trials. The cumulative numbers of events and rates of MIs and strokes over time were compared with those expected in the psoriasis and/or general populations. RESULTS: During the placebo-controlled period (12/20?weeks), five MACE were reported in 1582 Ustekinumab-treated patients [0�3%; 95% confidence interval (CI) 0�1-0�7%] compared with no events in 732 placebo-treated patients (0�0%; 95% CI 0�0-0�5%). MACE rates were stable over time during both the controlled and uncontrolled study periods, with 19 of 3117 Ustekinumab-treated patients (0�6%) experiencing 21 events for a combined event rate per 100 patient-years of follow-up of 0�44 (95% CI 0�27-0�67) through up to 3?years. Standardized incidence ratios for comparison of Ustekinumab clinical data with external data sources ranged from 0�34 to 0�52, suggesting no increased risk of MI or stroke in Ustekinumab-treated patients compared with the general U.S. and psoriasis populations. CONCLUSIONS: The totality of available clinical data suggests neither a detrimental nor a beneficial effect of Ustekinumab on serious CV events. Additional data are needed to define the net effect of Ustekinumab on CV events.
Tsen-fang Tsai - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to Ustekinumab results of the randomized double blind phase iii navigate trial
British Journal of Dermatology, 2018Co-Authors: R G Langley, Tsen-fang Tsai, Michael Song, Y Wasfi, B Randazzo, Susan Flavin, Jingzhi Jiang, Lluís PuigAbstract:SummaryBackground Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials. Objectives To evaluate the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis who had an inadequate response to Ustekinumab. Methods In this phase III, randomized, double-blind study, 871 patients received open-label Ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to Ustekinumab [Investigator's Global Assessment (IGA) ≥ 2] were randomized (double-blind) to guselkumab 100 mg or to continue Ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open-label Ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two-grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed. Results The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized Ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two-grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the Ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the Ustekinumab group. Conclusions Patients treated with Ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.
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The Association between Clinical Response to Ustekinumab and Immunogenicity to Ustekinumab and Prior Adalimumab
PloS one, 2015Co-Authors: Hsien-yi Chiu, Thomas Waitao Chu, Yu-pin Cheng, Tsen-fang TsaiAbstract:Background Immunogenicity due to antidrug antibodies (ADA) to tumor necrosis factor (TNF)-α antagonists is known to decrease treatment response. However, few studies have investigated ADA in Ustekinumab, an interleukin-12 and -23 antagonist, in a clinical setting. This study aimed to investigate the immunogenicity of Ustekinumab and its clinical consequences in psoriasis. Methods This prospective observational study enrolled 76 patients with plaque psoriasis who were treated with Ustekinumab for a minimum of 7 months. Blood samples were drawn just prior to scheduled Ustekinumab injection during clinic visits. Levels of anti-Ustekinumab antibody (AUA) and serum Ustekinumab concentration were measured respectively by radioimmunoassays and enzyme-linked immunoassays respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI). Results AUA was detected in 6.5% of patients after a mean of 13 months of treatment. Patients with positive AUA had significantly lower serum Ustekinumab concentrations (0.01 vs. 0.2 mg/L, p
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human leucocyte antigen cw6 as a predictor for clinical response to Ustekinumab an interleukin 12 23 blocker in chinese patients with psoriasis a retrospective analysis
British Journal of Dermatology, 2014Co-Authors: Hsien-yi Chiu, Yu-pin Cheng, Tingshun Wang, Changchuan Chan, Sungjan Lin, Tsen-fang TsaiAbstract:Summary Background Ustekinumab, an interleukin-12/23 inhibitor, is effective in the treatment of psoriasis. A recent Italian study showed more favourable response to Ustekinumab in patients with positive human leucocyte antigen (HLA)-Cw6. Nonetheless, there are differences in genetic susceptibility to psoriasis between races, and no studies have specifically assessed the candidate genetic markers in predicting therapy outcome in Chinese patients with psoriasis treated with Ustekinumab. Objectives To determine whether HLA gene polymorphisms can predict the response to Ustekinumab in Chinese patients with psoriasis. Methods Sixty-six patients with psoriasis treated with Ustekinumab were included in the study, and the effectiveness of Ustekinumab therapy was evaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI). Results More HLA-Cw6-positive patients achieved a PASI 75 response at week 4 compared with HLA-Cw6-negative patients (38% vs. 9%, P = 0·019). Similarly, at week 16, patients carrying the HLA-Cw6 allele showed a higher likelihood of achieving PASI 50, 75 and 90 than Cw6-negative patients, although this was not statistically significant. At week 28, a significantly higher percentage of HLA-Cw6-positive patients maintained PASI 90 response compared with Cw6-negative patients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele polymorphisms did not show significant associations with therapeutic response to Ustekinumab. Conclusions This pharmacogenetic study provides preliminary data indicating that positive HLA-Cw6 is associated with a good response to Ustekinumab treatment in Chinese patients with psoriasis.
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the safety profile of Ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis b or c
British Journal of Dermatology, 2013Co-Authors: Hsien-yi Chiu, Yu-pin Cheng, Chiehwen Chen, Mingshiou Wu, Tsen-fang TsaiAbstract:SummaryBackground Ustekinumab, an interleukin (IL)-12 and IL-23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of Ustekinumab in patients with viral hepatitis are limited. Objective To assess the safety profile of Ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C. Methods This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two Ustekinumab injections. Viral loads were measured at baseline and each time before the administration of Ustekinumab. Relevant clinical data were recorded. Results Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during Ustekinumab treatment. No viral reactivation was observed in the three occult HBV-infected patients (HBsAg-negative/hepatitis B core antibody-positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the Ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient. Conclusions Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti-viral prophylaxis, the risk/benefit of Ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high-risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation.
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the safety of Ustekinumab treatment in patients with moderate to severe psoriasis and latent tuberculosis infection
British Journal of Dermatology, 2012Co-Authors: Tsen-fang Tsai, Craig L Leonardi, Philippe Szapary, Michael Song, T Kato, Y Wasfi, Yaungkaung Shen, Japanese Ustekinumab Study GroupsAbstract:Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12/23 p40 to treat psoriasis. The IL-12 pathway is also important in regulating immunity to Mycobacterium tuberculosis. Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in Ustekinumab-treated patients with psoriasis. Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of Ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON®-TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis. Results At baseline, 101/2898 (3·5%) non-Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and Ustekinumab-treated patients, as well as between Ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and Ustekinumab-treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and Ustekinumab groups through week 12. The rate of INH-related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline. Conclusions Across five trials of Ustekinumab-treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.
Anthony Buisson - One of the best experts on this subject based on the ideXlab platform.
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Long-term efficacy and safety of Ustekinumab in 122 refractory Crohn's disease patients: a multicentre experience
Alimentary pharmacology & therapeutics, 2018Co-Authors: Pauline Wils, B. Flourié, Yoram Bouhnik, Pierre Michetti, Hedia Brixi, Anne Bourrier, Matthieu Allez, Bernard Duclos, Mélanie Serrero, Anthony BuissonAbstract:Background Long-term outcome of Ustekinumab in Crohn's disease (CD) has not been evaluated. Aim To evaluate the long-term efficacy and safety of Ustekinumab and identify the predictive factors of Ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients. Methods We performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous Ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued Ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery. Results Eighty-eight of the 122 (72%) CD patients beginning Ustekinumab from March 2011 to December 2014, responded to Ustekinumab and were followed up until November 2016. Median time on Ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continued Ustekinumab with a clinical response and 38 (43%) stopped treatment (32 for failure, five for remission and one for pregnancy). Endoscopic response was observed in 82% of patients with endoscopic evaluation and mucosal healing in 39%. Ustekinumab failure-free persistence rates were 78% at 12 months, 66% at 24 months and 55% at 36 months. No predictive factor of Ustekinumab failure-free persistence was identified. One severe adverse event was observed (anal adenocarcinoma). Conclusion In this cohort of refractory CD patients receiving long-term Ustekinumab therapy, more than 50% of patients continued Ustekinumab treatment with no loss of response, intolerance or surgery and with a good safety profile.
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subcutaneous Ustekinumab provides clinical benefit for two thirds of patients with crohn s disease refractory to anti tumor necrosis factor agents
Clinical Gastroenterology and Hepatology, 2016Co-Authors: Pauline Wils, Yoram Bouhnik, Pierre Michetti, Hedia Brixi, Anne Bourrier, Matthieu Allez, Bernard Flourie, Jean-charles Grimaud, B Duclos, Anthony BuissonAbstract:Background & Aims Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous Ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. Methods We performed a retrospective observational study, collecting data from the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of Ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. Results Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving Ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from Ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14–25.77; P=.03). Over a median follow-up period of 9.8 months (inter-quartile range, 5.3–14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of Ustekinumab were 93% and 68%, respectively. Conclusions Almost two thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from Ustekinumab therapy, not requiring steroids for up to 12 months afterward. While we await results from ongoing trials, Ustekinumab can be considered for use in these patients.
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Subcutaneous Ustekinumab Provides Clinical Benefit for Two-Thirds of Patients With Crohn’s Disease Refractory to Anti-Tumor Necrosis Factor Agents
Clinical Gastroenterology and Hepatology, 2016Co-Authors: Pauline Wils, Yoram Bouhnik, Pierre Michetti, Hedia Brixi, Anne Bourrier, Matthieu Allez, Bernard Duclos, Bernard Flourie, Jean-charles Grimaud, Anthony BuissonAbstract:Background & Aims Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous Ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. Methods We performed a retrospective observational study, collecting data from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of Ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. Results Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving Ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from Ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14–25.77; P=.03). Over a median follow-up period of 9.8 months (inter-quartile range, 5.3–14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of Ustekinumab were 93% and 68%, respectively. Conclusions Almost two thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from Ustekinumab therapy, not requiring steroids for up to 12 months afterward. While we await results from ongoing trials, Ustekinumab can be considered for use in these patients.
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Efficacy and safety of brodalumab in patients with psoriasis who had inadequate responses to Ustekinumab: subgroup analysis of two randomized phase III trials.
The British journal of dermatology, 2018Co-Authors: Richard G Langley, Radhakrishnan Pillai, Mark Lebwohl, Andrew Blauvelt, Sylvia Hsu, Shipra Rastogi, April W. Armstrong, S. K. Tyring, Robert J. IsraelAbstract:Background Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has demonstrated superior efficacy and safety over Ustekinumab as induction therapy for moderate-to-severe psoriasis. Objectives To evaluate the efficacy and safety of brodalumab through week 52 in patients who had inadequate responses to Ustekinumab. Methods A subgroup analysis of the phase III AMAGINE-2/-3 double-blind randomized controlled trials was performed. Participants were aged 18-75 years and had a Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment score ≥ 3 and involvement of ≥ 10% body surface area. The studies were registered at ClinicalTrials.gov: AMAGINE-2, NCT01708603; AMAGINE-3, NCT01708629. Results At baseline, patients with or without prior biologic experience who had an adequate response at week 16 on Ustekinumab or brodalumab had lower rates of involved body surface area, PASI, prior biologic use, psoriatic arthritis and body mass index than patients who experienced inadequate response at or after week 16. Among patients who experienced inadequate response to Ustekinumab, those rescued with brodalumab had PASI ≥ 75%, ≥ 90% and 100% improvement response rates of 72·6%, 58·1% and 36·3%, respectively, at week 52 compared with 61·7%, 25·5% and 5·4%, respectively, in patients who continued Ustekinumab. Exposure-adjusted rates of treatment-emergent adverse events were similar among patients rescued with brodalumab (377·3 adverse events per 100 patient-years) and those who remained on Ustekinumab (389·9 adverse events per 100 patient-years). Conclusions Among patients who experienced inadequate responses to Ustekinumab, rescue with brodalumab improved skin clearance outcomes compared with continuing Ustekinumab.
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impact of previous biologic use on the efficacy and safety of brodalumab and Ustekinumab in patients with moderate to severe plaque psoriasis integrated analysis of the randomized controlled trials amagine 2 and amagine 3
British Journal of Dermatology, 2018Co-Authors: Kim Papp, Radhakrishnan Pillai, Mark Lebwohl, Kenneth B. Gordon, Richard G Langley, Alice B Gottlieb, Shipra Rastogi, Robert J. IsraelAbstract:BACKGROUND Biologics are being used increasingly to treat moderate-to-severe psoriasis. Efficacy may differ in patients with previous exposure to biologics. OBJECTIVES To investigate the impact of previous biologic exposure on the efficacy and safety of brodalumab and Ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS Two placebo- and Ustekinumab-controlled phase III clinical trials. There was an initial 12-week induction phase where patients were treated with brodalumab [210 mg or 140 mg every 2 weeks (Q2W)], Ustekinumab or placebo. Efficacy end points included ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. Ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout. RESULTS In total, 493 patients [334 (27%) brodalumab 210 mg Q2W and 159 (26%) Ustekinumab] had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40·9% and 39·5% of biologic-naive and -experienced patients achieved PASI 100 at week 12, compared with 21·1% and 17·0% with Ustekinumab (both P < 0·001). In patients where prior biologics had been successful or failed, 41·7% and 32·0% achieved PASI 100, compared with 21·1% and 11·3% with Ustekinumab. Tolerability was similar, and did not appear to be influenced by previous treatment with biologics. CONCLUSIONS The efficacy of brodalumab 210 mg Q2W was similar regardless of prior biological therapy (P = 0·31, 0·32 and 0·64 for PASI 75, 90 and 100, respectively). Almost twice as many patients achieved PASI 100 or complete clearance with brodalumab at week 12 compared with Ustekinumab; the differences were most noticeable where previous biologics had failed. Both treatments were well tolerated.
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Impact of previous biologic use on the efficacy and safety of brodalumab and Ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3.
The British journal of dermatology, 2018Co-Authors: Kim Papp, Radhakrishnan Pillai, Mark Lebwohl, Kenneth B. Gordon, Richard G Langley, Alice B Gottlieb, Shipra Rastogi, Robert J. IsraelAbstract:BACKGROUND Biologics are being used increasingly to treat moderate-to-severe psoriasis. Efficacy may differ in patients with previous exposure to biologics. OBJECTIVES To investigate the impact of previous biologic exposure on the efficacy and safety of brodalumab and Ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS Two placebo- and Ustekinumab-controlled phase III clinical trials. There was an initial 12-week induction phase where patients were treated with brodalumab [210 mg or 140 mg every 2 weeks (Q2W)], Ustekinumab or placebo. Efficacy end points included ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. Ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout. RESULTS In total, 493 patients [334 (27%) brodalumab 210 mg Q2W and 159 (26%) Ustekinumab] had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40·9% and 39·5% of biologic-naive and -experienced patients achieved PASI 100 at week 12, compared with 21·1% and 17·0% with Ustekinumab (both P
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long term safety experience of Ustekinumab in patients with moderate to severe psoriasis part i of ii results from analyses of general safety parameters from pooled phase 2 and 3 clinical trials
Journal of The American Academy of Dermatology, 2012Co-Authors: Mark Lebwohl, Newman Yeilding, Cynthia Guzzo, Christopher E M Griffiths, Craig L Leonardi, J C Prinz, Philippe Szapary, Ming Chun Hsu, Bruce E StroberAbstract:Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. Objective To evaluate overall pooled study data to assess the safety profile of Ustekinumab through 3 years of treatment. Methods Cumulative safety data were pooled from studies in 3117 Ustekinumab-treated patients. Results During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with Ustekinumab 45 mg (57.6%), or with Ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; Ustekinumab 45 mg: 66.0%; and Ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between Ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. Limitations Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 Ustekinumab-treated patients were treated for 2 or more years. Conclusions The safety profile of continued Ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.
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cardiovascular safety of Ustekinumab in patients with moderate to severe psoriasis results of integrated analyses of data from phase ii and iii clinical studies
British Journal of Dermatology, 2011Co-Authors: Kristian Reich, Newman Yeilding, Cynthia Guzzo, Mark Lebwohl, Philippe Szapary, Ming Chun Hsu, R G Langley, Christopher E M GriffithsAbstract:BACKGROUND: Patients with psoriasis are believed to be at an increased risk of cardiovascular (CV) morbidity, and the effect of biological agents on CV safety is not fully understood. OBJECTIVES: To evaluate the effect of Ustekinumab on CV events using detailed analyses of pooled data from the phase II/III clinical studies of its use in moderate to severe psoriasis. METHODS: The incidence of major adverse CV events [MACE: myocardial infarction (MI), stroke or CV death] is reported. Meta-analyses using risk difference and odds ratio estimates are presented based on data collected during the placebo-controlled period of Ustekinumab trials. The cumulative numbers of events and rates of MIs and strokes over time were compared with those expected in the psoriasis and/or general populations. RESULTS: During the placebo-controlled period (12/20?weeks), five MACE were reported in 1582 Ustekinumab-treated patients [0�3%; 95% confidence interval (CI) 0�1-0�7%] compared with no events in 732 placebo-treated patients (0�0%; 95% CI 0�0-0�5%). MACE rates were stable over time during both the controlled and uncontrolled study periods, with 19 of 3117 Ustekinumab-treated patients (0�6%) experiencing 21 events for a combined event rate per 100 patient-years of follow-up of 0�44 (95% CI 0�27-0�67) through up to 3?years. Standardized incidence ratios for comparison of Ustekinumab clinical data with external data sources ranged from 0�34 to 0�52, suggesting no increased risk of MI or stroke in Ustekinumab-treated patients compared with the general U.S. and psoriasis populations. CONCLUSIONS: The totality of available clinical data suggests neither a detrimental nor a beneficial effect of Ustekinumab on serious CV events. Additional data are needed to define the net effect of Ustekinumab on CV events.
