Leonardi CL, Kimball AB, Papp KA et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665-1674

Probity Medical Research, Waterloo and University of Western Ontario, London, ON, Canada.
The Lancet (Impact Factor: 45.22). 05/2008; 371(9625):1675-84. DOI: 10.1016/S0140-6736(08)60726-6
Source: PubMed

ABSTRACT 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, 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.

Download full-text


Available from: Lisa Tomasko Dooley, Aug 17, 2015
1 Follower
  • Source
    • "Arg1, arginase-1; Fizz1, found in inflammatory zone 1; IL-4, Interleukin-4; NOS2, nitric oxide synthase 2. cerebral A␤ 42 levels, as well as increase of synaptophysin levels and Nissl-positive cell densities in the SAMP8 mice. These findings raise the question of whether monoclonal p40 antibodies (ustekinumab and briakinumab), which have already been approved by the US Food and Drug Administration for the treatment of psoriasis or undergone clinical validation in psoriatic arthritis, Crohn's disease and multiple sclerosis [48] [49] [50] [51] [52], should be tested in randomized, controlled trials for the treatment of AD in the future. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progressively increased proinflammatory status is a major characteristic of the aging process and associated with age-related diseases such as Alzheimer's diseases (AD). However, the regulation and role of common proinflammatory cytokines, including interleukin-12 (IL-12) and IL-23, in the aged brain are still unclear. Using the senescence-accelerated mouse prone-8 (SAMP8) model, we screened the cerebral expression of IL-12/23 in 3-, 7-, and 11-month-old mice and observed that their levels in the brain were upregulated during aging. To further examine whether the heightened activation of inflammatory cytokines may contribute to age-related brain dysfunction, we employed direct in vivo infusion of nonviral small interfering RNA (siRNA) to knock down the common IL-12/23 signaling subunit p40 in the brain. We found that these p40-deficient mice had significantly decreased cerebral amyloid-β levels, reduced synaptic and neuronal loss, and reversed cognitive impairments. Furthermore, in vivo delivery of a neutralizing p40-specific antibody likewise ameliorated AD-associated pathology and cognitive deficits in SAMP8 mice. Thus, our data indicate that the upregulated cerebral IL-12/23 during aging is involved in age-associated brain dysfunction and point to the modulation of IL-12/23 signaling molecule p40 as a promising strategy for the development of an AD therapy.
    Journal of Alzheimer's disease: JAD 09/2013; 38(3). DOI:10.3233/JAD-131148 · 4.15 Impact Factor
  • Source
    • "Targeting the specific subset of T cells or their effector cytokines that are critical to the pathogenesis of DLE is a strategy for the design of new therapeutic agents, as has been done for other cutaneous autoimmune diseases. Psoriasis, now known to be a Th17-mediated disease, is a clear example; ustekinumab, a monoclonal antibody that blocks Th17-and Th1- related pathways (Leonardi et al., 2008; Papp et al., 2008) was recently approved for the treatment of psoriasis, and two IL-17/Th17-pathway inhibitors were recently shown to be efficacious in clinical trials (Leonardi et al., 2012; Papp et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Discoid lupus erythematosus (DLE) is the most common skin manifestation of lupus. Despite its high frequency in systemic lupus in addition to cases without extracutaneous manifestations, targeted treatments for DLE are lacking, likely due to a dearth of knowledge of the molecular landscape of DLE skin. Here, we profiled the transcriptome of DLE skin in order to identify signaling pathways and cellular signatures that may be targeted for treatment purposes. Further comparison of the DLE transcriptome to that of psoriasis, a useful reference given our extensive knowledge of molecular pathways in this disease, provided a framework to identify potential therapeutic targets. Although a growing body of data supports a role for IL-17 and Th17 cells in systemic lupus, we show a relative enrichment of IFN-γ-associated genes without that for IL-17-associated genes in DLE. Extraction of T cells from the skin of DLE patients identified a predominance of IFN-γ-producing Th1 cells and an absence of IL-17-producing Th17 cells, complementing the results from whole skin transcriptomic analyses. These data therefore support investigations into treatments for DLE that target Th1 cells or the IFN-γ signaling pathway.Journal of Investigative Dermatology accepted article preview online, 14 June 2013; doi:10.1038/jid.2013.269.
    Journal of Investigative Dermatology 06/2013; 134(1). DOI:10.1038/jid.2013.269 · 6.37 Impact Factor
  • Source
    • "Etanercept studies vs. placebo and the study of Saurat 2008 17 for adalimumab had as an inclusion criterion a PASI > 10, while the other trials had a baseline PASI > 12. Trials with both values were considered adequate because the majority of recent clinical trials of biologics used these cut-offs as an inclusion criterion for defining moderate-to-severe psoriasis. However, some authors define moderate psoriasis as one with a PASI between 7 and 12, and severe psoriasis as disease with PASI > 12. 22 Finlay 23 suggests the 'rule of 10', for defining severe psoriasis: PASI > 10, BSA > 10 and a score of Dermatology Life Quality Index (developed by the same author) > 10. Leonardi 2003, 21 Papp 2005 24 and van den Kerkhof 2008 19 compare the PASI at week 24 for etanercept and at week 12 for placebo, as the placebo group changed to active treatment at that point. We believe that the comparison is valid as PASI score is not expected to change in the placebo group. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Psoriasis is a chronic skin disease for which there is an increasing range of treatment options. Biological agents (ustekinumab, adalimumab, infliximab and etanercept) are indicated for moderate-to-severe plaque-type psoriasis in adults who fail to respond to, have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate and PUVA Unfortunately, with new drugs, the pivotal trials leading to their licensing are often placebo-controlled trials rather than comparative trials vs. established therapies. Therefore, inference on comparative effectiveness of the newer agents must be derived indirectly, through estimation of effects of the new agents vs. a common comparator. The objective of this study is to compare the relative efficacy of the biological agents through a systematic review of the indirect clinical trial evidence. A systematic literature search was performed for clinical trials of biological agents in psoriasis. Pivotal, randomized, double-blind, controlled (placebo) trials using intention-to-treat analysis were selected for detailed analysis. Trials must include PASI 75 as a primary end point. The indirect comparison was performed using the method of Bucher adjusted with the ITC calculator (Indirect Treatment Comparisons of the Canadian Agency for Drugs and Technologies in Health), etanercept being the reference drug. We defined delta value for therapeutic equivalence as a difference in the efficacy of 25% among the different treatment options. Fourteen studies (four for ustekinumab, three for adalimumab, three for infliximab and four for etanercept) were included. The indirect comparison results reveal that ustekinumab, adalimumab and infliximab were statistically superior to etanercept with an absolute risk difference for PASI 75 of 12% (95% CI = 5·9-18%), 11% (95% CI = 5·3-16·7%) and 24% (29·7-18·3%) respectively. However, in all situations, the 95% confidence interval does not achieve clinical relevance as no delta exceeds the previously set value (25%). Ustekinumab, adalimumab, infliximab and etanercept can be regarded as clinical equivalents for the treatment of psoriasis. Choice between these agents therefore depends on their relative safety profiles, individual contra-indications and cost effectiveness.
    Journal of Clinical Pharmacy and Therapeutics 04/2013; 38(2):121-30. DOI:10.1111/jcpt.12044 · 1.53 Impact Factor
Show more