Michael P. Heffernan

Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials

BACKGROUND Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. METHODS In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. FINDINGS Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. INTERPRETATION Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. FUNDING Eli Lilly and Co.

A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting ∼2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20–30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24–q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain–containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.

Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial

Background Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). Methods A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided. Results There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups. Conclusions Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

Adalimumab treatment is associated with improvement in health‐related quality of life in psoriasis: Patient‐reported outcomes from a Phase II randomized controlled trial

Background: Psoriasis substantially impairs the health‐related quality of life (HRQOL) of patients, and a comprehensive evaluation of treatment includes HRQOL measures. Objective: To assess the impact of adalimumab on patient‐reported outcomes (PROs) of patients with moderate to severe psoriasis. Methods: In a Phase II, randomized, controlled trial, the efficacy and safety of two dosages of adalimumab (40 mg weekly or every other week) versus placebo were assessed for 12 weeks in the treatment of moderate to severe plaque psoriasis. Patients completed the Dermatology Life Quality Index (DLQI), Short‐Form 36 (SF‐36) Health Survey, and EuroQOL‐5D (EQ‐5D) at baseline and 12 weeks. The primary endpoint was the percentage of patients achieving a ⩾75% reduction in the Psoriasis Area and Severity Index score (PASI 75). Investigators assessed PASI and Physicians Global Assessment (PGA) scores. Results: Adalimumab patients (either dosage) displayed significantly greater improvements versus placebo patients in DLQI, EQ‐5D, and SF‐36 Mental Component Summary scores, as well as in Bodily Pain, Vitality, Social Functioning, Role–Emotional, and Mental Health domains. The adalimumab 40‐mg weekly group also reported significantly greater improvements in SF‐36 Physical Component Summary scores versus the placebo group. Conclusion: Both adalimumab dosages were efficacious in improving dermatology‐specific and general PROs in patients with moderate to severe psoriasis.

A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis.

BACKGROUND Patients with moderate to severe plaque psoriasis demonstrated positive responses to ixekizumab, an anti-interleukin-17A monoclonal antibody, in a phase-II, randomized, placebo-controlled trial. OBJECTIVE We sought to evaluate long-term efficacy and safety of ixekizumab. METHODS After receiving 10, 25, 75, or 150 mg of ixekizumab or placebo during randomized, placebo-controlled trial, patients with less than 75% improvement from baseline on the Psoriasis Area and Severity Index (PASI) score (PASI75) entered open-label extension (OLE); patients with PASI75 or higher entered a treatment-free period (weeks 20-32), then entered OLE after meeting response criteria. During OLE, patients received 120 mg of subcutaneous ixekizumab every 4 weeks. RESULTS In all, 120 patients entered OLE; 103 completed 52 weeks or more of treatment. Overall, 77% of patients achieved PASI75 at week 52 (nonresponder imputation). Patients who responded to treatment in the randomized, placebo-controlled trial maintained a high-level response by week 52 of OLE (PASI75 = 95%; 90% improvement from baseline on the PASI score = 94%; 100% improvement from baseline on the PASI score = 82%). Irrespective of dose in the randomized, placebo-controlled trial, each group had similar response rates at week 52 of OLE. The exposure-adjusted incidence rate for adverse events was 0.47 and for serious adverse events was 0.06 per patient-year during OLE. LIMITATIONS No control group, small sample sizes, and bias toward retention of patients with positive responses limit interpretation. CONCLUSION A high proportion of patients responded to ixekizumab therapy and maintained clinical responses over 1 year of treatment with no unexpected safety signals.

Efficacy and safety of open-label ixekizumab treatment in Japanese patients with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis.

Ixekizumab, an anti‐IL‐17A monoclonal antibody, demonstrated a high level of efficacy in moderate‐to‐severe plaque psoriasis (PP) patients.

The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: Results of a prospective, multicenter, open-label study

BACKGROUND In patients with psoriasis and inadequate response (IR) to tumor necrosis factor-α antagonist treatment, the incremental benefit of switching to another tumor necrosis factor-α antagonist is unknown. OBJECTIVE We sought to evaluate the clinical response to an etanercept-to-infliximab switch in patients with psoriasis and IR to etanercept. METHODS Adults with moderate-to-severe plaque psoriasis and IR to etanercept (≥ 4 months) were eligible for this open-label study (called PSUNRISE). Patients had a Physician Global Assessment (PGA) score of at least 2 (mild) on a 5-point scale with etanercept, with or without concomitant oral systemic methotrexate or cyclosporine at baseline and during the study. Patients received intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22. PGA was used to evaluate efficacy at week 10 (primary end point) and week 26 (durability). Safety was evaluated through the end of the study. RESULTS Of 215 patients, only 10 received concomitant immunomodulators. At week 10, 65.4% of patients (138 of 211; 95% confidence interval 58.6%-71.8%) achieved a PGA score of clear (0) or minimal (1) (primary end point). This response was durable through week 26, at which time 61.3% (122 of 199; 95% confidence interval 54.2%-68.1%) achieved a PGA score of clear (0) or minimal (1). There were no unexpected side effects or safety concerns. LIMITATIONS This was an open-label, 26-week study; an incremental change of 1 PGA point, even mild to minimal, was considered clinically significant, as most psoriasis practitioners seek to achieve minimal psoriasis or clear skin. CONCLUSION After switching to infliximab, a substantial proportion of patients with psoriasis and IR to etanercept experienced rapid and durable improvement.

Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis

Scalp and nail psoriasis have a major impact on quality of life and are traditionally resistant to therapy. Ixekizumab is a monoclonal antibody that targets IL‐17A, a key cytokine in psoriasis pathogenesis.

Off-label uses of rituximab in dermatology.

ABSTRACT:  Since its approval in 1997 by the FDA, rituximab has been approved for use in certain B‐cell lymphomas and treatment‐resistant rheumatoid arthritis. Over the past 10 years, many case reports have indicated rituximabs efficacy in a number of inflammatory conditions in dermatology. This article includes a review of the mechanism of action, dosing, and side effect profile, as well as a review of the current literature on off‐label uses of the CD20+ B‐cell antagonist rituximab.

Efficacy and Safety of Adalimumab Treatment in Patients with Moderate to Severe Psoriasis: A Double-Blind, Randomized Clinical Trial

Background Tumor necrosis factor-alpha (TNF-α) is pivotal in the pathogenesis of psoriasis, an immune-mediated disease. Adalimumab is a fully human, IgG1 monoclonal antibody that inhibits TNF-α. Objectives The aims of this study were to assess the efficacy and safety of adalimumab therapy for patients with moderate to severe plaque psoriasis and evaluate the duration of treatment response after withdrawal from or dosage reduction of adalimumab therapy. Methods In this multicenter, randomized, double-blind, placebo-controlled study, patients with moderate to severe plaque psoriasis received 12-week, open-label therapy with subcutaneous adalimumab, consisting of 80 mg of adalimumab at weeks 0 and 1, followed by 40 mg weekly at weeks 2–11. At week 12, patients who had an improvement in Psoriasis Area and Severity Index (PASI) score of ≥50% were randomized to blinded therapy and received either adalimumab 40 mg every other week (eow) or placebo for an additional 12 weeks. Results A total of 148 patients enrolled. Clinical response was rapid, with a PASI 50 response rate of 28% at week 2 of adalimumab therapy. At week 12, 91.9% (136/148) of patients had achieved ≥50% reduction in PASI (PASI 50) vs. baseline, 76.4% (113/148) had achieved PASI 75, and 47.3% (70/148) had achieved PASI 90. Of patients who were randomized to placebo at week 12, 30.9% (21/68) experienced a relapse (<PASI 50 improvement vs. baseline) by week 24, compared with 16.2% (11/68) of patients who received adalimumab 40 mg eow. In addition, 48.5% (33/68) of patients who were randomized to placebo at week 12 were PASI 75 responded at week 24, compared with 67.6% (46/68) of patients randomized to adalimumab 40 mg eow (p=0.032). And, 27.9% (19/68) of patients who were randomized to placebo at week 12 were PASI 90 responders at week 24, compared with 47.1% (32/68) of patients randomized to adalimumab 40 mg eow (p=0.028). Adalimumab was generally well-tolerated, and the rates of adverse events were comparable between the adalimumab and placebo groups. Conclusions Weekly adalimumab therapy rapidly improved psoriasis during an initial 12-week period. Improvement was sustained in most, but not all patients, despite dosage reduction to every other week. No patients randomized to adalimumab withdrawal (placebo at week 12) experienced rebound, and most maintained >PASI 50 improvement, relative to baseline, during the 3 months following adalimumab discontinuation. Overall, greater efficacy rates at week 24 were observed for patients randomized to continuous adalimumab therapy than for patients who were withdrawn from therapy at week 12.