Long-term efficacy and safety of brodalumab in the treatment of psoriasis: 120-week results from the randomized, double-blind, placebo- and active comparator-controlled phase 3 AMAGINE-2 trial.

BACKGROUND: Randomized controlled trials have shown the efficacy and safety of brodalumab in patients with moderate to severe plaque psoriasis. OBJECTIVE: To evaluate the efficacy and safety of brodalumab through 120 weeks of treatment in the AMAGINE-2 trial. METHODS: Patients received ustekinumab through week 52 followed by brodalumab 210 mg every 2 weeks, continuous brodalumab 210 mg every 2 weeks, or any dose of brodalumab. Efficacy data were reported through 120 weeks by using observed data, last observation carried forward, and nonresponder imputation analyses. RESULTS: Of patients who received brodalumab 210 mg every 2 weeks, 84.4%, 75.6%, and 61.1% achieved 75%, 90%, and 100% improvement from baseline in Psoriasis Area and Severity Index at 120 weeks (observed data analysis), respectively. Patients who received brodalumab 210 mg every 2 weeks after receiving ustekinumab through 52 weeks achieved a similar skin clearance response as patients who received continuous brodalumab 210 mg every 2 weeks. Safety through 120 weeks was comparable to that of the blinded study periods. LIMITATIONS: A large number of discontinuations toward the end of the study (31% in the final 6 months) were due to early termination and led to differences between observed data and nonresponder imputation results. CONCLUSIONS: Brodalumab is well tolerated and showed robust efficacy for more than 2 years.

Effects of Apremilast on Pruritus and Skin Discomfort/Pain Correlate With Improvements in Quality of Life in Patients With Moderate to Severe Plaque Psoriasis.

Pruritus and skin discomfort/pain negatively impact health-related quality of life (HRQoL). The effects of apremilast, an oral phosphodiesterase inhibitor, on pruritus, skin discomfort/pain, and patient global assessment of psoriasis disease activity (PgAPDA) were assessed in moderate/severe chronic plaque psoriasis patients in the phase 3 ESTEEM trials. Significant improvements in pruritus and skin discomfort/pain observed at Week 2 with apremilast versus placebo (both studies, p < 0.0001) were sustained through Week 32. Among apremilast-treated patients, improvements in pruritus visual analog scale (VAS) scores correlated with Dermatology Life Quality Index scores (rs = 0.55 [Week 16], rs≥0.51 [Week 32]; both studies, p < 0.001). PgAPDA correlated with improvements in pruritus (rs≥0.56 [Week 16]; rs≥0.53 [Week 32]; both studies, p < 0.001) and skin discomfort/pain (rs ≥0.54 [Week 16]; rs≥0.53 [Week 32]; both studies, p < 0.001) VAS scores. Apremilast provided rapid and sustained improvement in pruritus and skin discomfort/pain, symptoms not typically captured in psoriasis assessments (e.g., PASI) that contribute significantly to patients' disease severity and HRQoL perceptions.

Update on TNF Inhibitors in Dermatology.

Emerging data describe new potential indications for tumor necrosis factor (TNF) inhibitors in dermatology, including pediatric psoriasis and hidradenitis suppurativa. New biosimilar TNF agents are in late stages of development and may be available in the United States in the near future. Biosimilar agents are similar but not identical to available TNF inhibitors, and approval requires extensive analytic, toxicity, pharmacokinetic, pharmacodynamic, and clinical testing. Semin Cutan Med Surg 35(supp6):S104-S106.

The role of TNF inhibitors in psoriatic disease.

In contrast to many other diseases, modern psoriasis therapy has a fairly brief history. Until about 15 years ago, clinicians and their patients had few options, with limited ability to rein in the disease process.The success of antifolate methotrexate in the treatment of rheumatoid arthritis (RA) led to clinical evaluation and adoption of the agent, a principal form of treatment for psoriasis, which, like RA, has its origin based in inflammation. The introduction of tumor necrosis factor-α inhibitors marked the beginning of the biologic era of psoriasis therapy. Also borrowed from the field of rheumatology, biologic therapy has evolved from improved understanding of the molecular basis of the disease process. An increased recognition of comorbid conditions that often accompany psoriasis, particularly psoriatic arthritis, can complicate clinical management. Dermatologists and other clinicians who treat psoriasis continue to benefit from insights gained in the field of rheumatology.

Therapeutic development in psoriasis.

Advances in molecular biology have provided the basis for development of new therapeutic approaches to psoriasis. New, more effective therapies target specific molecules in the inflammatory cascade involved in the pathogenesis of psoriasis.The biologic era of psoriasis therapy began with inhibitors of T-cell activation, tumor necrosis factor-α, and interleukin (IL)-12/23. Continued investigation has led to therapies and therapeutic candidates that target IL-17, IL-23, phosphodiesterase-4, and isomers of Janus kinase.

A series of critically challenging case scenarios in moderate to severe psoriasis: a Delphi consensus approach.

Clinical trials for systemic psoriasis therapy typically enroll healthy patients and exclude patients with cardiovascular disease, latent tuberculosis, liver disease, histories of malignancies, viral infections, children, and pregnant or breast-feeding women. Physicians often require guidance for optimum management of severe psoriasis in patients that have a combination of underlying disease states. To provide treatment recommendations for complex psoriasis scenarios, a consensus panel comprising 15 experts in psoriatic disease convened to review and discuss available evidence-based data and to arrive at a consensus for treatment options of difficult cases. An application of the Delphi Method was used to select case scenarios, provide medical treatment options, present the case study with existing medical evidence, and anonymously vote on treatment options. The top 10 treatment options were ranked and statistically analyzed to compare the differences between treatments. The final rankings and analysis provide guidance for practical, safe, and efficacious treatment options in a number of complex psoriasis scenarios.

Management of moderate to severe plaque psoriasis (part I): clinical update on antitumor necrosis factor agents.

Psoriasis is an immunologic disorder mediated by T cells and proinflammatory cytokines. Novel biologic therapies, targeted at key pathogenic steps, have been developed and provide efficacy without the potential end-organ toxicity induced by traditional therapies. The biologic therapies currently approved for treatment of psoriasis are classified into 2 categories, as defined by their mechanism of action: inhibition of tumor necrosis factor (TNF) (etanercept, infliximab, adalimumab) and modulation of pathogenic activated T cells (alefacept, efalizumab). This review has been prepared in 2 parts: Part 1 focuses on anti-TNF agents and includes new data that have become available through increased clinical experience and use in eligible patients. Part 2 will present new data on T-cell modulators, new molecules in development, and considerations for optimal therapeutic selection for treatment of patients with psoriasis (Journal of Drugs in Dermatology, March 2009).

Management of moderate to severe plaque psoriasis (part 2): clinical update on T-cell modulators and investigational agents.

This second part of a 2-part review on the use of biologics for treatment of patients with psoriasis is focused on currently approved therapies that work through modulation of T cells: alefacept, a leukocyte function-associated antigen 3-immunoglobulin G fusion molecule; and efalizumab, an anti-CD11 humanized antibody. Efficacy and safety data from pivotal clinical trials are summarized and new data are presented for these biological agents, and considerations for optimal therapeutic selection are discussed. Clinical data from investigational agents currently in development are also reviewed. One of these new agents is ustekinumab, a humanized antibody that targets interleukins 12 and 23 and inhibits the differentiation of Th17 cells, a recently identified subset of CD4+ T-helper cells.

Safety of efalizumab therapy in patients with moderate to severe psoriasis: an open-label extension of a phase IIIb trial.

BACKGROUND: Psoriasis is a chronic autoimmune disease characterized by infiltration of the dermis and epidermis by activated T cells and the hyperproliferation and abnormal differentiation of keratinocytes. It is a life-long disease with alternating periods of remission and recurrence. Efalizumab is a humanized, recombinant, T-cell targeting monoclonal antibody, approved for use in adults with chronic moderate to severe plaque psoriasis. OBJECTIVE: To assess the safety of continued or newly initiated treatment with efalizumab for up to 48 weeks in patients with psoriasis who were treated previously with efalizumab or placebo. METHODS: This study was an open-label, 48-week extension of a previously published 12-week, randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase IIIb study, carried out in the US and Canada between 24 October 2002 and 2 July 2004. Patients were followed and treated at the study clinic in an outpatient setting and also were trained to self-administer the drug at home. Patients comprising individuals with chronic moderate to severe plaque psoriasis who had completed the 12-week, placebo-controlled segment of the study were eligible for enrolment in the extension phase. Of the 686 patients enrolled in the study, 636 (92.7%) enrolled in the open-label extension of the study, 418 of whom had received 12 weeks of efalizumab therapy and 218 of whom had received 12 weeks of placebo. All patients entering the open-label phase of the study received efalizumab 1 mg/kg/wk for an additional 48 weeks, for a maximum exposure of up to 60 weeks. Safety was evaluated by an assessment of adverse events, including infections and serious adverse events. RESULTS: The rate of withdrawal due to adverse events remained low throughout the trial, ranging from 1.2% to 6.6% during the 12-week segments of the open-label extension phase of the trial. The incidence of adverse events decreased with increased exposure to efalizumab; the incidence during the initial 12 weeks of exposure to efalizumab was 79.0% compared with 72.9% for patients exposed to placebo. Patients treated with efalizumab for 13-24 weeks, 25-36 weeks, 37-48 weeks and 49-60 weeks experienced adverse events at an incidence of 66.8%, 54.3%, 49.6% and 48.5%, respectively. The incidence of serious adverse events ranged from 1.6% to 3.5% during the 12-week segments of efalizumab therapy, compared with an incidence of 3.4% for placebo-treated patients. The incidence of infection ranged from 9.9% to 14.7% during the 12-week segments of efalizumab therapy, compared with an incidence of 19.1% for placebo-treated patients. Malignancies were reported with an incidence of

Safety of Adalimumab Dosed Every Week and Every Other Week: Focus on Patients with Hidradenitis Suppurativa or Psoriasis.

BACKGROUND: Adalimumab is approved for the treatment of hidradenitis suppurativa (HS), plaque psoriasis, and other inflammatory conditions. OBJECTIVE: Our objective was to examine the safety of adalimumab administered every other week (EOW) and every week (EW) in patients with HS and psoriasis and to investigate informative data from non-dermatologic indications. METHODS: The safety of adalimumab 40-mg EOW versus EW dosing was examined during placebo-controlled and open-label study periods in patients with HS (three studies), psoriasis (two studies), Crohn's disease (six studies), ulcerative colitis (three studies), and rheumatoid arthritis (one study). RESULTS: No new safety risks or increased rates of particular adverse events (AEs) were identified with EW dosing. In patients with HS or psoriasis, the overall safety of adalimumab 40-mg EOW and EW was generally comparable. In studies of adalimumab for non-dermatologic indications, including Crohn's disease, ulcerative colitis, and rheumatoid arthritis, the overall AE rates were similar for EW and EOW dosing. CONCLUSION: In patients with HS or psoriasis, the safety of adalimumab EW and EOW was comparable and consistent with the expected adalimumab AE profile. The safety of adalimumab EW dosing in patients with dermatologic conditions is supported by data comparing adalimumab EW and EOW dosing for Crohn's disease, ulcerative colitis, and rheumatoid arthritis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00918255, NCT01468207, NCT01468233, NCT00645814, NCT00077779, NCT00055497, NCT01070303, NCT00195715, NCT00348283, NCT00385736, NCT00408629, and NCT00573794.

Reductions in healthcare resource utilization in psoriatic arthritis patients receiving etanercept therapy: results from the educate trial.

The Experience Diagnosing, Understanding Care, and Treatment with Enbrel (EDUCATE) trial is a phase IV, 24-week, multicenter, open-label study of etanercept 50 mg weekly in the treatment of psoriatic arthritis (PsA) in community dermatology clinics. In this study, patients with active PsA and moderate to severe plaque psoriasis have measurable uses of healthcare resources at baseline, reflecting a burden of illness. Etanercept significantly reduced healthcare resource utilization, absenteeism, and caregiver assistance in PsA patients after 24 weeks of treatment. These results could translate into savings on both direct and indirect costs and improvements in health-related quality of life for patients with PsA.

Infection-free Clinical Response Among Patients With Hidradenitis Suppurativa Who Were Treated With Adalimumab: Results from Two Phase 3 Studies.

OBJECTIVE: The objective of this study is to assess the rates of infection-free achievement of hidradenitis suppurativa clinical response (HiSCR) using integrated data from 2 phase 3, placebo-controlled trials, PIONEER I and II. MATERIALS AND METHODS: Analyses from the first 12 weeks of both studies were examined. Patients were randomized to receive adalimumab (ADA) or placebo, and they then were assessed in the clinic at weeks 0, 2, 4, 8, and 12. All reports of an adverse or serious adverse event and infection were classified as treatment-emergent adverse events (TEAEs). The HiSCR was evaluated as the primary endpoint; infection-free HiSCR was also evaluated. RESULTS: Treatment-emergent adverse events were observed in 55.4% of the ADA group and 64.4% of the placebo (P < .023). The rates of serious TEAEs and infection-related TEAEs were slightly less in the ADA group compared with the placebo group. A significantly higher percentage of ADA-treated patients achieved HiSCR at week 12 compared with placebo (P < .001). At each visit during the study's 12 weeks, a greater proportion of ADA-treated patients achieved infection-free HiSCR compared with patients treated with placebo (P < .001). Mean durations of HiSCR and infection-free HiSCR were significantly longer in ADA-treated patients when compared with placebo-treated patients (P < .001). CONCLUSIONS: Results of this integrated analysis indicate that patients with hidradenitis suppurativa who received a short duration of ADA treatment experienced better combined efficacy and similar safety compared with placebo. Further studies investigating longer ADA treatment may demonstrate further improvements in duration of infection-free clinical response.

Successful treatment of hand and foot psoriasis with efalizumab therapy.

Hand and foot psoriasis can appear in a plaque-type or pustular-type form. Any form of psoriasis that occurs on the hands and feet can have a debilitating effect on the patient's daily functions. Here we present a case series of patients with plaqueor pustular-type hand and foot psoriasis whose conditions were successfully managed with the biologic agent efalizumab. In many of these patients, the disease was refractory to multiple systemic psoriasis treatments. Treatment with efalizumab was effective and well-tolerated, with few adverse events. Many of the patients described here reported an improvement in both their physical functioning and health-related quality of life. The efficacy of efalizumab in treating these cases of hand and foot psoriasis suggests that it may provide therapeutic benefit.

Overview of biologic agents in medicine and dermatology.

Three agents have recently been approved by the Food and Drug Administration for the treatment of chronic plaque psoriasis: alefacept, efalizumab, and etanercept. The field of dermatology has now entered a new era, joining other disciplines of medicine that have been using biologic agents for decades. These new therapies offer psoriatic patients the potential for safe and effective long-term management of this disease. This article reviews how an increased understanding of the pathophysiology of psoriasis led to the development of these products.

Systemic therapies for psoriasis: understanding current and newly emerging therapies.

The treatment of moderate to severe psoriasis is a rapidly expanding area. Recent insights into the pathogenesis of this disease as a T-cell mediated process has led to a greater understanding of the mechanisms of action of conventional FDA-approved systemic therapies such as methotrexate, cyclosporine, acitretin, and psoralen with ultraviolet A phototherapy. It has also led to the development of rationally targeted therapies against key components of the immune process critical in the generation of the psoriatic plaque. Safety and efficacy data from clinical studies of 4 biologic agents furthest along in their development are reviewed. These results are promising, adding to the armamentarium for treating this disease.

A Delphi Consensus Approach to Challenging Case Scenarios in Moderate-to-Severe Psoriasis: Part 1.

INTRODUCTION: Traditional clinical trials in psoriasis exclude a significant proportion of patients with complex disease and comorbidities. A consensus panel of 14 experts in the field of psoriasis was formed to conduct a Delphi method exercise to identify difficult-to-treat psoriasis clinical scenarios and to rank treatment approaches. METHODS: The exercise consisted of both survey questionnaires and a live meeting to review and discuss current data (as of 2009, when the exercise was conducted) and arrive at a consensus for optimal treatment options. Seventy difficult treatment scenarios were identified, and the top 24 were selected for discussion at the live meeting. RESULTS: Six of the 24 discussed case scenarios are presented in this article (another five are presented in Part 2): (1) psoriasis with human papilloma virus-induced cervical or anogenital dysplasia; (2) concomitant psoriasis and systemic lupus erythematosus; (3) severe psoriatic nail disease causing functional or emotional impairment; (4) psoriasis therapies that potentially reduce cardiovascular morbidity and mortality; (5) older patients (≥65 years of age) with psoriasis; and (6) severe scalp psoriasis that is unresponsive to topical therapy. CONCLUSION: The Delphi exercise resulted in guidelines for practicing physicians to utilize when confronted with challenging patients with psoriasis.