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.
Summary 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.
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.
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.
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.
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.
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.
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).
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%.
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.
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.
Background
People with genital psoriasis may avoid close social interactions (hugs, handshakes, kisses, touching others, or being touched), which can have a significant impact on quality of life. ...Ixekizumab, an interleukin 17A antagonist, demonstrated rapid and persistent improvement in moderate‐to‐severe genital psoriasis through 52 weeks in a phase 3 trial (IXORA‐Q).
Objectives
To evaluate general touch avoidance (TA) in patients with moderate‐to‐severe genital psoriasis treated with ixekizumab through 52 weeks in the IXORA‐Q trial.
Methods
In IXORA‐Q (NCT02718898), adult patients received 80 mg ixekizumab every 2 weeks (IXE Q2W, N = 75) or placebo (PBO, N = 74) for 12 weeks. At Week 12, all patients received open‐label 80 mg ixekizumab every 4 weeks (IXE Q4W) through Week 52, with an opportunity to escalate dosing to Q2W at Weeks 24, 28, or 40. Patients used a numeric rating scale (NRS) to self‐report the degree of TA experienced over the past 2 weeks (score of 0 not at all to 10 very much). Outcomes included TA NRS score change from baseline and the proportion of patients achieving a TA NRS score of 0 through Week 52. Correlations between TA NRS scores and psoriasis outcomes were also examined.
Results
Mean (standard deviation) baseline TA NRS score was 2.7 (3.3) for IXE Q2W and 3.0 (3.5) for PBO. Among patients with a baseline TA NRS score >0, mean (standard deviation) change from baseline at Week 52 (where a lower score indicates greater improvement) and the proportion of patients who achieved a TA NRS score of 0 at Week 52 were −4.4 (3.2) 78.0% for patients treated continuously with ixekizumab (Q2W then Q4W, N = 41) and −4.1 (3.6) 62.5% for PBO/IXE Q4W (N = 40). TA NRS score improved in parallel with the majority of psoriasis outcomes examined, with the strongest positive association between the TA NRS score and Dermatology Life Quality Index total score.
Conclusions
Among patients with moderate‐to‐severe genital psoriasis, ixekizumab treatment achieves continued sustained improvement in general TA to 52 weeks.
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.
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.
Summary 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.
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.
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