Long-term Efficacy and Safety of Up to 108 Weeks of Ixekizumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis: The IXORA-PEDS Randomized Clinical Trial.

Importance: About 1% of children and adolescents worldwide are affected by plaque psoriasis. Objective: To evaluate the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis. Design, Setting, and Participants: This multicenter randomized clinical trial (IXORA-PEDS) evaluated pediatric patients with plaque psoriasis. Participants were aged 6 years to younger than 18 years; had moderate to severe psoriasis, which was defined as Psoriasis Area and Severity Index (PASI) of 12 or higher, static Physician's Global Assessment (sPGA) score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline; were candidates for phototherapy or systemic therapy; or had psoriasis that was not adequately controlled by topical therapies. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021. Interventions: Pediatric patients were randomized 2:1 to receive either a weight-based dose of ixekizumab every 4 weeks or placebo. After a 12-week placebo-controlled period, patients entered a 48-week, open-label ixekizumab maintenance period (weeks 12-60), followed by an extension period that lasted through 108 weeks. A substudy evaluated the randomized withdrawal of ixekizumab after week 60. Main Outcomes and Measures: Efficacy outcomes at week 108 included the percentage of patients achieving 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline; an sPGA score of 0 or 1 or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale. Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs, serious AEs, and AEs of special interest, as well as improvement from baseline in a range of challenging body areas. Missing data for categorical outcomes were imputed using modified nonresponder imputation. Results: A total of 171 patients (mean [SD] age, 13.5 [3.04] years; 99 female children [57.9%]) were randomized to either ixekizumab (n = 115) or placebo (n = 56). Of 166 patients who entered the maintenance period, 139 (83.7%) completed week 108 of the trial. Primary and gated secondary end points were sustained through week 108, with patients achieving PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]). Fifty-five patients (78.5%) reported an Itch Numeric Rating Scale improvement of 4 points or higher. In patients who received ixekizumab, at week 108, clearance of nail psoriasis was reported in 68.1% (n = 28), clearance of palmoplantar psoriasis was reported in 90.0% (n = 10), clearance of scalp psoriasis was reported in 76.2% (n = 83), and clearance of genital psoriasis was reported in 87.5% (n = 24). There were no new safety findings during weeks 48 to 108 of the trial, including no new cases of inflammatory bowel disease or candida infection. Conclusions and Relevance: Results of this study showed improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis among pediatric patients who received ixekizumab, and these response rates were sustained through week 108 of the trial. Safety of ixekizumab was consistent with previously reported findings in this population and the known safety profile of this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT03073200.

Ixekizumab Improved Patient-Reported Genital Psoriasis Symptoms and Impact of Symptoms on Sexual Activity vs Placebo in a Randomized, Double-Blind Study.

INTRODUCTION: Genital psoriasis (GenPs) is common and distressing for patients, but is often not discussed with physicians, and no previous clinical trials have assessed the effects of biologics specifically on GenPs and its associated symptoms. AIM: To report results for novel patient-reported outcomes (PROs) for the assessment of symptoms and the sexual impact of GenPs before and after treatment in the IXORA-Q study. METHODS: IXORA-Q (NCT02718898) was a phase III, randomized, double-blind, placebo-controlled study of ixekizumab (80 mg/2 weeks after 160-mg initial dose) vs placebo for GenPs. Men and women ≥18 years old with moderate-to-severe GenPs and body surface area (BSA) ≥1% were assessed through 12 weeks. MAIN OUTCOME MEASURE: GenPs symptoms were assessed using the 8-item Genital Psoriasis Symptoms Scale (GPSS), Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), and Genital Psoriasis Sexual Impact Scale (GPSIS) (validation data presented in the supplemental materials), and the Dermatology Life Quality Index (DLQI) item 9. RESULTS: For patients receiving ixekizumab (N = 75) vs placebo (N = 74), statistically significant improvement in GenPs symptoms were seen from week 1 onward (GPSS total and individual items, all P < .005). Sexual activity avoidance owing to GenPs symptoms (GPSIS) decreased significantly with ixekizumab from week 4 onward (all P <.005), whereas impact of sexual activity on GenPs improved significantly with ixekizumab at weeks 2-8 (all P < 0.05). Ixekizumab resulted in significant improvement vs placebo by week 1 onward in limitations on frequency of sexual activity owing to GenPs (GenPs-SFQ item 2). Sexual difficulties caused by skin (DLQI item 9) decreased significantly with ixekizumab from week 2 onward (all P < .001). CLINICAL IMPLICATIONS: Both GenPs symptoms and impact on sexual activity improved rapidly and significantly with ixekizumab vs placebo through 12 weeks in patients with moderate-to-severe GenPs and BSA ≥1%. STRENGTH & LIMITATIONS: To our knowledge, this is the first phase III, randomized, placebo-controlled, double-blinded clinical trial to evaluate the effect of any treatment on the symptoms and sexual impact related to GenPs. The study did not include an active comparator owing to the lack of any well-established treatment for moderate-to-severe GenPs, and the period assessed herein was of relatively short duration. CONCLUSION: These validated PRO measures may aid in future clinical studies of GenPs and in facilitating discussions of GenPs symptoms and their impact between patients and clinicians. Yosipovitch G, Foley P, Ryan C. Ixekizumab improved patient-reported genital psoriasis symptoms and impact of symptoms on sexual activity vs placebo in a randomized, double-blind study. J Sex Med 2018;15:1645-1652.

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION: Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2).

BACKGROUND: Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis. OBJECTIVE: Assess long-term safety of oral apremilast in psoriasis patients. METHODS: Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. RESULTS: The 0 to ≥156-week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156-week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52-week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. LIMITATIONS: This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. CONCLUSIONS: Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

Efficacy of Secukinumab on Moderate-to-severe Plaque Psoriasis Affecting Different Body Regions: a Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: The impact of psoriasis varies with the body region affected. In addition, patients have different perceptions of disease improvement and treatment satisfaction based on the location of skin clearance with treatment. The monoclonal antibody secukinumab selectively targets interleukin-17A-a central cytokine of psoriasis-and provides rapid and sustained clearance for moderate-to-severe psoriasis affecting all body regions. The objective of this study was to evaluate the efficacy of secukinumab on moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. METHODS: Data were pooled from four phase 3 studies. To be included in the analysis for each body region, patients were required to have a Psoriasis Area and Severity Index (PASI) score ≥12 for that body region and psoriasis covering ≥10% of the surface area of that region. Secukinumab was administered at Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48. RESULTS: Across the trunk, upper limbs, and lower limbs, initial PASI subscore responses were sustained to Week 52. At Week 52, trunk (T) PASI 90/100 responses were achieved by 78.4%/71.1% of patients receiving secukinumab 300 mg, respectively, and by 66.3%/56.9% of patients receiving secukinumab 150 mg, respectively. At Week 52, upper limb (UL) PASI 90/100 responses were achieved by 67.3%/59.1% of patients receiving secukinumab 300 mg, respectively, and by 50.3%/43.3% of patients receiving secukinumab 150 mg, respectively. At Week 52, lower limb (LL) PASI 90/100 responses were achieved by 63.9%/55.3% of patients receiving secukinumab 300 mg, respectively, and by 45.1%/36.4% of patients receiving secukinumab 150 mg, respectively. A 50% reduction in mean PASI subscore occurred after 2.8, 2.9, and 3.4 weeks with secukinumab 300 mg on the trunk, upper limbs, and lower limbs, respectively. CONCLUSION: Secukinumab provided robust and sustained efficacy for moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. FUNDING: Novartis Pharmaceuticals Corporation. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01365455, NCT01358578, NCT01555125, and NCT01636687.

Use of biologic agents in combination with other therapies for the treatment of psoriasis.

Psoriasis is a chronic inflammatory skin disorder, which is associated with a significant negative impact on a patient's quality of life. Traditional therapies for psoriasis are often not able to meet desired treatment goals, and high-dose and/or long-term use is associated with toxicities that can result in end-organ damage. An improved understanding of the involvement of cytokines in the etiology of psoriasis has led to the development of biologic agents targeting tumor necrosis factor (TNF)-α and interleukins (ILs)-12/23. While biologic agents have improved treatment outcomes, they are not effective in all individuals with psoriasis. The combination of biologic agents with traditional therapies may provide improved therapeutic options for patients who inadequately respond to a single drug or when efficacy may be increased with supplementation of another treatment. In addition, combination therapy may reduce safety concerns and cumulative toxicity, as lower doses of individual agents may be efficacious when used together. This article reviews the current evidence available on the efficacy and safety of combining biologic agents with systemic therapies (methotrexate, cyclosporine, or retinoids) or with phototherapy, and the combination of biologic agents themselves. Guidance is provided to help physicians identify situations and the characteristics of patients who would benefit from combination therapy with a biologic agent. Finally, the potential clinical impact of biologic therapies in development (e.g., those targeting IL-17A, IL-17RA, or IL-23 alone) is analyzed.

Psoriasis in children and women: addressing some special needs.

Psoriasis is a lifelong, chronic disease that affects all ages. For some, psoriasis begins in childhood, and education of both pediatric patients and their parents is essential to successful and safe disease management. Systemic treatment of children is challenging as no evidence-based guidelines have been developed to date. When treating women with psoriasis, clinicians should also consider psychosocial effects. In patients of childbearing age, treatment options depend on the patients' choices regarding pregnancy.

Proceedings of the 5th annual perspectives in rheumatic diseases.

OBJECTIVES: Update on rheumatic diseases and their intersection with dermatology. RESULTS: This continuing medical education conference included more than 25 presentations and interactive sessions from leading experts in managing rheumatic diseases, comorbid conditions and related dermatologic diseases. Multiple areas were discussed, including: treating newly diagnosed rheumatoid arthritis; comparing Biologics in rheumatoid arthritis; examining changed approaches to treating SLE, psoriasis, psoriatic arthritis, ankylosing spondylitis, gout and vasculitis. Also visited were new understandings regarding chronic pain and osteoporosis. CONCLUSIONS: Multiple presentations and interactive sessions from leading experts in the management of rheumatic diseases emphasized the interconnection between rheumatology and dermatology. Practical management approaches to both specialties and their sequelae were discussed. Additional content from the conference is available at www.globalacademycme.com and through Rheumatology News at www.rheumatologynews.com.

Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial.

BACKGROUND: Apremilast, a small-molecule inhibitor of phosphodiesterase 4, works intracellularly to modulate proinflammatory and anti-inflammatory mediator production, and doses of 20 mg twice daily have shown efficacy in the treatment of moderate to severe plaque psoriasis in a 12-week phase 2 study. We assessed the clinical efficacy and safety of different doses of apremilast in the treatment of patients with moderate to severe plaque psoriasis. METHODS: In this phase 2b, multicentre, randomised, placebo-controlled, dose-ranging study, patients (aged ≥18 years) with moderate to severe psoriasis were randomly assigned (in a 1:1:1:1 ratio) to receive oral placebo or apremilast 10, 20, or 30 mg twice daily at 35 US and Canadian sites between Sept 24, 2008, and Oct 21, 2009. At week 16, patients in the placebo group were assigned apremilast 20 or 30 mg twice daily until week 24. Randomisation was generated with a permuted-block randomisation list via interactive voice response system. For the first 16 weeks, treatment assignment was concealed from both investigators and participants. During weeks 16-24, investigators and participants all knew that treatment was active, but the dose was concealed. The primary endpoint was the proportion of patients achieving at least 75% reduction from baseline psoriasis area and severity index (PASI-75) at week 16. Analyses were by intention to treat; missing values were imputed by last-observation-carried-forward. This trial is registered with ClinicalTrials.gov, number NCT00773734. FINDINGS: 89 patients were randomly assigned apremilast 10 mg, 87 apremilast 20 mg, and 88 apremilast 30 mg twice daily; 88 were assigned placebo. At week 16, PASI-75 was achieved in five patients (6%) assigned placebo, ten (11%) assigned apremilast 10 mg, 25 (29%) assigned 20 mg, and 36 (41%) assigned 30 mg. Apremilast 10 mg did not differ significantly from placebo in achievement of the endpoint (odds ratio 2·10; 95% CI 0·69-6·42); for both apremilast 20 mg (6·69; 2·43-18·5; p<0·0001) and apremilast 30 mg (11·5; 4·24-31·2; p<0·0001), the differences from placebo were significant. Most adverse events (96%) were mild or moderate; at least 5% of patients had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests. INTERPRETATION: Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis. Our results support continuing, longer-term studies. FUNDING: Celgene Corporation.

The ACCEPT study: ustekinumab versus etanercept in moderate-to-severe psoriasis patients.

The first biologic therapy for psoriasis was approved in 2003. Other approvals followed, including TNF-α inhibitors, and in addition to providing new treatment options that were greatly needed, these therapies increased our understanding of the immunopathogenesis of psoriasis. Clinical trial activity increased, but all biologic trials were placebo controlled with no active comparators. In 2009, ustekinumab, a new agent that targets the p40 subunit of cytokines IL-12 and IL-23, was approved. In 2010, the Active Comparator (CNTO1275/Enbrel) Psoriasis Trial (ACCEPT) was published, the first active comparator trial of psoriasis biologic agents, comparing ustekinumab and the TNF antagonist etanercept. Here, we describe the results of the ACCEPT trial and offer an expert commentary on the results and implications for psoriasis treatment and research.

A review of malignancies observed during efalizumab (Raptiva) clinical trials for plaque psoriasis.

BACKGROUND: Psoriasis is a chronic, incurable immune-mediated disease. Most therapies used for moderate to severe psoriasis are immunosuppressive. Agents that depress immune function, including traditional psoriasis therapies, have been associated with an increased incidence of malignancies. Efalizumab is a recombinant monoclonal immunoglobulin G1 (IgG1) antibody approved for use in psoriasis patients. OBJECTIVES: To evaluate the incidence of malignancy in patients receiving efalizumab during clinical trials compared with placebo-treated patients, psoriasis patients from external cohorts and the general US population. METHODS: Patient data were pooled from multiple phase III placebo-controlled, open-label efalizumab clinical trials, and the incidence rate of reported malignancies was calculated as a function of patient years of observation. The results for the efalizumab-treated patients were compared with the data on psoriasis patients from insurance claims databases and a registry of events in the general population. RESULTS: The efalizumab- and placebo-treated patients had similar incidence rates of malignancy, including lymphoproliferative disease, solid tumor, malignant melanoma and nonmelanoma skin cancer. The incidence of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, in patients receiving efalizumab or placebo was elevated relative to the external databases. CONCLUSIONS: These results suggest that efalizumab treatment does not increase a patient's risk for malignancy. The difference observed with nonmelanoma skin cancer may be due to biases introduced by the clinical trial methodology. Additional patient observation is necessary to ascertain whether a link exists between efalizumab therapy and nonmelanoma skin cancer above that normally observed in psoriasis patients.

The efficacy of multiple courses of alefacept in patients with moderate to severe chronic plaque psoriasis.

Among patients with psoriasis who did not achieve Psoriasis Area and Severity Index 50 during the first course of alefacept therapy, 53% achieved Psoriasis Area and Severity Index 50 during the second course (odds ratio [95% confidence interval] vs placebo 2.30 [1.26-4.19]). Alefacept provided incremental efficacy over 5 successive 12-week treatment courses.