Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn’s Disease: An Integrated Analysis of Phase II/III Clinical Development Programs

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Abstract

Introduction

Theoretical risks of biologic agents remain under study.

Objective

The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.

Methods

Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn’s disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).

Results

Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2–128.7) versus 129.4 (120.9–138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2–101.5] vs. 115.3 [109.9–121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3–125.9] vs. 107.3 [102.0–112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3–0.7] vs. 0.3 [0.0–1.1]), malignancies (0.4 [0.2–0.6] vs. 0.2 [0.0–0.8]), and deaths (0.1 [0.0–0.3] vs. 0.0 [0.0–0.4]) were rare across indications.

Conclusions

Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.

Trial Registrations

ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

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Most cited references 24

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Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

William J Sandborn, Christopher R Gasink, Long-Long Gao … (2012)

In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. 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 compared 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 compared 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. Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists 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 number, NCT00771667.).

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Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

Kim Papp, Richard Langley, Mark G. Lebwohl … (2008)

Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437. All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group. Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

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Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Christopher Ritchlin, Proton Rahman, Arthur Kavanaugh … (2014)

Objective Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

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Author and article information

Contributors

Subrata Ghosh: 0121 371 8047 , s.ghosh@bham.ac.uk

Lianne S. Gensler: Lianne.Gensler@ucsf.edu

Zijiang Yang: zyang43@its.jnj.com

Chris Gasink: CGasink@its.jnj.com

Soumya D. Chakravarty: schakr66@its.jnj.com

Kamyar Farahi: KFarahi@its.jnj.com

Paraneedharan Ramachandran: pramach4@its.jnj.com

Elyssa Ott: EOtt1@its.jnj.com

Bruce E. Strober: strober@uchc.edu

Journal

Journal ID (nlm-ta): Drug Saf

Journal ID (iso-abbrev): Drug Saf

Title: Drug Safety

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0114-5916

ISSN (Electronic): 1179-1942

Publication date (Electronic): 9 February 2019

Publication date PMC-release: 9 February 2019

Publication date (Print): 2019

Volume: 42

Issue: 6

Pages: 751-768

Affiliations

[1 ]ISNI 0000 0004 1936 7486, GRID grid.6572.6, Institute of Translational Medicine and NIHR Birmingham Biomedical Research Centre, , University of Birmingham, ; Office 04, Ground Floor, ITM, North Block, Heritage Building, Mindelson Way, Edgbaston, Birmingham, B15 2TH UK

[2 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Axial Spondyloarthritis Clinic, , University of California San Francisco, ; 400 Parnassus Ave., Floor B1, San Francisco, CA 94143 USA

[3 ]ISNI 0000 0004 0389 4927, GRID grid.497530.c, Janssen Research & Development, LLC, ; 1400 McKean Road, Spring House, PA 19477 USA

[4 ]ISNI 0000 0004 0389 4927, GRID grid.497530.c, Janssen Scientific Affairs, LLC, ; 800 Ridgeview Drive, Horsham, PA 19044 USA

[5 ]ISNI 0000 0001 2181 3113, GRID grid.166341.7, Drexel University College of Medicine, ; 219 N. Broad Street, Floor 9, Philadelphia, PA 19107 USA

[6 ]ISNI 0000000419370394, GRID grid.208078.5, Department of Dermatology, , University of Connecticut Health Center, ; 21 South Road, 2nd Floor, Farmington, CT 06030 USA

[7 ]GRID grid.415267.3, Probity Medical Research, ; 135 Union Street E, Waterloo, ON N2J 1C4 Canada

Article

Publisher ID: 797

DOI: 10.1007/s40264-019-00797-3

PMC ID: 6520311

PubMed ID: 30739254

SO-VID: 8277c02e-9a31-408b-8f6d-1882fb8b544a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100005205, Janssen Research and Development;

Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn’s Disease: An Integrated Analysis of Phase II/III Clinical Development Programs

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Abstract

Introduction

Objective

Methods

Results

Conclusions

Trial Registrations

Related collections

Core Readings in Statistical Mediation Analysis

Most cited references 24

Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

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