Original article
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

https://doi.org/10.1016/j.jaad.2011.06.011Get rights and content

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.

Introduction

Moderate-to-severe psoriasis is a chronic immune-mediated disorder that may require long-term therapy. The safety profile of biologic agents with short-term use for psoriasis has been established in clinical studies for etanercept,1, 2, 3 alefacept,4, 5, 6 infliximab,7, 8, 9 adalimumab,10, 11, 12 and ustekinumab.13, 14, 15 Longer exposures, however, are needed to evaluate potential cumulative toxicities and rare or long-latency adverse safety events that may not become apparent in short-term studies. Data from long-term use of anti–tumor necrosis factor (TNF) agents in rheumatoid arthritis and Crohn’s disease can provide insight into the long-term safety profile of this class of agents.16, 17, 18, 19, 20, 21, 22

Ustekinumab (Stelara, Janssen Biotech, Inc, Horsham, PA), the most recent biologic agent approved for treatment of adult patients with moderate-to-severe psoriasis, is a fully human monoclonal antibody that binds to the p40 subunit of interleukin (IL)-12 and IL-23 and is the first anti-IL-12/23 antibody approved for any indication. The efficacy and safety of ustekinumab were evaluated in more than 3000 patients enrolled in one Phase 2 trial and 3 Phase 3 trials, 2 of which (PHOENIX 113 and PHOENIX 214) were designed to collect efficacy and safety data through 5 years.

Safety findings pertaining to ustekinumab treatment in patients with moderate-to-severe psoriasis have been previously reported through week 36 (Phase 2),23 week 52 (PHOENIX 2),14 week 64 (ACCEPT),15 and week 76 (PHOENIX 1).13 In the current report, we analyze the pooled safety data through 3 years of treatment with ustekinumab from these 4 clinical trials.13, 14, 15, 23 A total of 1852 patients were exposed to ustekinumab for at least 1 year, 1247 patients were exposed for at least 2 years, and 157 patients were exposed for at least 3 years, to date (Fig 1). This report focuses on the overall accrued safety profile, while targeted adverse events (serious infections and malignancies) and cardiovascular events24 are discussed in greater detail in separate publications.

Section snippets

Patients and study design

The safety data presented in this report were pooled from one Phase 223 and 3 Phase 3 (PHOENIX 1,13 PHOENIX 2,14 and ACCEPT15) trials, which were randomized, blinded, controlled studies of ustekinumab treatment in patients with moderate-to-severe psoriasis. Written informed consent was obtained from each patient before any study-specific procedures, and study protocols were approved by the institutional review board or ethics committee at each site.

The trial designs and patient eligibility

Patients’ characteristics

A total of 3219 patients were enrolled in one Phase 2 and 3 Phase 3 ustekinumab psoriasis trials, and 3117 patients received at least one dose of ustekinumab (Fig 1). Patient demographic and baseline disease characteristics have been previously reported13, 14, 15, 23 and are summarized in Table II. The baseline patient characteristics were similar among treatment groups within each trial and across the trials (Table II). The majority of patients were white (92.0%) men (68.5%), and the mean age

Discussion

Ustekinumab is the most recent biologic agent approved for the treatment of moderate-to-severe psoriasis and the first to neutralize both IL-12 and IL-23. Data from more than 3000 patients from one Phase 2 study and 3 Phase 3 studies through up to 3 years of treatment showed no clear safety signals during the controlled period of these studies and a stable safety profile comparable between ustekinumab doses through up to 3 years of follow-up.

Based on pooled study data, the rates of adverse

References (34)

  • C.L. Leonardi et al.

    Etanercept as monotherapy in patients with psoriasis

    N Engl J Med

    (2003)
  • K.A. Papp et al.

    A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction

    Br J Dermatol

    (2005)
  • A.B. Gottlieb et al.

    Etanercept monotherapy in patients with psoriasis: a summary of safety, based on an integrated multistudy database

    J Am Acad Dermatol

    (2006)
  • C.N. Ellis et al.

    Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes

    N Engl J Med

    (2001)
  • M. Lebwohl et al.

    An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis

    Arch Dermatol

    (2003)
  • A. Menter et al.

    A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis

    J Am Acad Dermatol

    (2007)
  • J.H. Saurat et al.

    Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION)

    Br J Dermatol

    (2008)
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    Funded by Centocor Research & Development, Inc, a division of Johnson & Johnson Pharmaceutical Research & Development, LLC, Malvern, PA.

    Conflicts of interest: A complete listing may be found in the Appendix.

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