Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.

BACKGROUND: Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS: In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS: At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)--150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)--than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS: Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.).

Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.

The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.

Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.

BACKGROUND: IL-23 expression is increased in psoriatic lesions and might regulate TH17 T-cell counts in patients with psoriasis. OBJECTIVES: We sought to test a novel IL-23-specific therapeutic agent for the treatment of psoriasis. METHODS: In this randomized, double-blind, placebo-controlled study the safety, tolerability, and clinical response of guselkumab, an anti-IL-23-specific mAb, were evaluated in patients with moderate-to-severe plaque psoriasis. A total of 24 patients were randomized to receive a single dose of placebo or 10, 30, 100, or 300 mg of guselkumab. Clinical response was assessed by using the Psoriasis Area and Severity Index (PASI). Additionally, histologic analysis and gene expression in skin biopsy specimens from guselkumab-treated patients were compared with those from placebo-treated patients. RESULTS: At week 12, 50% (10 mg), 60% (30 and 100 mg), and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a 75% improvement in PASI scores from baseline compared with 0% of placebo-treated patients. Improvements in PASI scores were generally maintained through week 24 in all guselkumab-treated patients. The proportion of patients experiencing an adverse event was comparable between the combined guselkumab (13/20 [65.0%]) and placebo (2/4 [50.0%]) groups through week 24. Analysis of lesional and nonlesional skin biopsy specimens demonstrated decreases in epidermal thickness and T-cell and dendritic cell expression in guselkumab-treated patients compared with values seen in placebo-treated patients. At week 12, significant reductions in psoriasis gene expression and serum IL-17A levels were observed in guselkumab-treated patients. CONCLUSION: IL-23 inhibition with a single dose of guselkumab results in clinical responses in patients with moderate-to-severe psoriasis, suggesting that neutralization of IL-23 alone is a promising therapy for psoriasis.

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.

Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study.

BACKGROUND: Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediators. This phase II, multicenter, open-label study evaluated the efficacy, tolerability, and pharmacodynamics of apremilast in patients with recalcitrant plaque psoriasis.
METHODS: This multicenter, open-label study comprised four phases: pre-treatment (≤35 days), treatment (12 weeks), extension (12 weeks), and observational follow-up (4 weeks). Patients with recalcitrant plaque psoriasis received apremilast 20 mg BID for 12 weeks. Responders (≥75% improvement in Psoriasis Area and Severity Index [PASI-75]) continued treatment and non-responders (< PASI-75) were titrated to apremilast 30 mg BID through week 24. Efficacy assessments included change in static Physician's Global Assessment, PASI, and body surface area, and proportion of patients achieving PASI-50, PASI-75, and PASI-90. Other assessments included adverse events, lesional skin biopsies to assess changes in epidermal thickness, and immunohistochemistry to assess changes in peripheral blood subsets. RESULTS: A total of 30 patients were enrolled. At week 12, 67% of patients had a ≥1-point improvement in static Physician's Global Assessment, meeting treatment effect criterion. Mean percent decreases (improvements) from baseline were -59% for PASI score and -53% for body surface area. Most adverse events were mild. Median reduction in epidermal thickness was 34% at week 12 (P=0.083); five patients showed absence of keratin 16. Significant reductions in CD11c, CD3, and CD56 indicate that apremilast reduced myeloid dendritic cell, T-cell, and NK-cell or NK-T-cell infiltration into the epidermis and dermis. Reduced inflammatory leukocytes, with a pattern of broad, partial inhibition, suggested reduced IL-23/Th17 and Th22 response pathways. CONCLUSIONS: These results confirm apremilast's biological and clinical activity and support ongoing studies in psoriasis. Clinicaltrials.gov Identifier: NCT00521339.

Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratoses (AKs). Light-emitting diodes (LEDs) offer practical advantages when treating multiple lesions. OBJECTIVE: To evaluate the efficacy and tolerability of PDT using a LED and topical methyl aminolevulinate (MAL) for treatment of multiple AKs. METHODS AND MATERIALS: One hundred thirty-one patients with four to 10 non-pigmented, previously untreated thin or moderately thick AKs on the face or scalp were enrolled in this multicenter, double-blind, randomized, placebo-controlled study. MAL or matching placebo cream was applied to the débrided lesion surface for 3 hours before illumination with noncoherent red light (630 nm, light dose 37 J/cm(2)). Treatment was repeated 1 week later. RESULTS: Efficacy was evaluated in 57 patients with 418 lesions treated with MAL PDT and 58 with 414 lesions treated with placebo PDT. Sixteen patients were excluded as protocol violators (not randomized). MAL PDT was superior (p< .001) to placebo PDT in lesion complete response rates (83.3%, 95% confidence interval (CI)=79.3-86.7%, vs 28.7%, 95% CI=24.4-33.4%) and patient complete response rates (all lesions showing complete response; 68.4%, 95% CI=54.8-80.1% vs 6.9%, 95% CI=1.9-16.7%). CONCLUSIONS: Topical MAL PDT using a LED is an effective treatment for multiple AKs.

Hydrocortisone butyrate 0.1% lotion in the treatment of atopic dermatitis in pediatric subjects.

BACKGROUND: Hydrocortisone butyrate (HCB) is currently marketed as a cream, ointment, and solution. A new lotion formulation of hydrocortisone butyrate 0.1% (Locoid lotion) has been developed and evaluated. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of HCB 0.1% lotion compared to the vehicle in subjects aged 3 months to less than 18 years with mild to moderate atopic dermatitis (AD). METHODS: In this multicenter double-blind study, 284 subjects with mild to moderate AD were randomized 1:1 to receive HCB 0.1% lotion or the vehicle for a duration of 4 weeks. "Treatment success" was defined as those subjects with a final Physician Global Assessment (PGA) score of 0 or 1 that had at least a 2-point reduction in the PGA score from baseline to day 29. Safety was assessed by monitoring adverse events. RESULTS: Analyses of the final PGA score showed a significant treatment effect (P <.001) in favor of the HCB 0.1% lotion group. The safety profile of the HCB 0.1% lotion was also favorable. LIMITATIONS: The study did not assess the durability of the treatment effects (ie, safety and efficacy) after completion of the 4-week treatment period nor the potential need for longer term therapy given the chronic nature of AD. CONCLUSION: Results demonstrate the safety and efficacy of HCB 0.1% lotion in the treatment of mild to moderate AD in children 3 months to 18 years of age.

Etanercept as monotherapy in patients with psoriasis.

BACKGROUND: Inflammatory cytokines such as tumor necrosis factor (TNF) have been implicated in the pathogenesis of psoriasis. We evaluated the safety and efficacy of etanercept, a TNF antagonist, for the treatment of plaque psoriasis. METHODS: In this 24-week, double-blind study, 672 patients underwent randomization and 652 either received placebo or received etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary measure of clinical response was the psoriasis area-and-severity index. RESULTS: At week 12, there was an improvement from base line of 75 percent or more in the psoriasis area-and-severity index in 4 percent of the patients in the placebo group, as compared with 14 percent of those in the low-dose--etanercept group, 34 percent in the medium-dose--etanercept group, and 49 percent in the high-dose-etanercept group (P<0.001 for all three comparisons with the placebo group). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75 percent improvement in the psoriasis area-and-severity index in 25 percent of the patients in the low-dose group, 44 percent of those in the medium-dose group, and 59 percent in the high-dose group. The responses as measured by improvements in the psoriasis area-and-severity index were paralleled by improvements in global assessments by physicians and the patients and in quality-of-life measures. Etanercept was generally well tolerated. CONCLUSIONS: The treatment of psoriasis with etanercept led to a significant reduction in the severity of disease over a period of 24 weeks.

Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head.

BACKGROUND: A shorter dosing regimen of imiquimod for the treatment of actinic keratosis may be effective, with long-term clinical benefits. OBJECTIVE: Imiquimod in one or two shorter courses of treatment was evaluated. METHODS: Patients with actinic keratosis lesions on the head applied imiquimod or vehicle cream 3x/wk for 4 weeks (course 1). Patients with remaining lesions received another course of treatment. Complete and partial clearance rates were evaluated after course 1, after course 2 (overall), and 1 year later. RESULTS: Complete clearance rates were 26.8% (course 1) and 53.7% (overall). Partial clearance rates were 36.6% (course 1) and 61.0% (overall). One-year follow-up recurrence rates were 39% (imiquimod) and 57% (vehicle). LIMITATIONS: Blinded investigators may have been biased toward patients treated with imiquimod identified by treatment site reactions. CONCLUSION: Imiquimod 3x/wk in one or two courses of treatment appears to be effective for the treatment of actinic keratoses on the head, providing long-term clinical benefits. Some recurrences do occur, so long-term follow-up is recommended.

Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of 5% imiquimod cream compared with vehicle in the treatment of actinic keratosis (AK). DESIGN: Two phase 3 randomized, double-blind, parallel-group, vehicle-controlled studies. SETTING: Twenty-six ambulatory care offices, including dermatologists in private practice or research centers. PATIENTS: Four hundred ninety-two patients, 18 years and older, with 4 to 8 AK lesions in a 25-cm(2) treatment area on the face or the balding scalp were randomized; an additional 162 patients underwent screening but were ineligible. INTERVENTIONS: Patients applied 5% imiquimod (Aldara) or vehicle cream to the treatment area once daily, 3 times per week, for 16 weeks, followed by an 8-week posttreatment period. MAIN OUTCOME MEASUREMENTS: Complete clearance rate (proportion of patients at the 8-week posttreatment visit with no clinically visible AK lesions in the treatment area), partial clearance rate (proportion of patients at the 8-week posttreatment visit with a >/=75% reduction in the number of baseline AK lesions in the treatment area), and frequency and severity of adverse events and local skin reactions were measured. RESULTS: Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. CONCLUSION: The 5% imiquimod cream dosed 3 times weekly for 16 weeks is safe and effective for the treatment of AK.

A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.

UNLABELLED: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51­89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01154101.

A randomized trial of etanercept as monotherapy for psoriasis.

OBJECTIVE: To determine safety and efficacy of monotherapy with etanercept. DESIGN: Randomized, double-blind, placebo-controlled, multicenter study. SETTING: Outpatient, ambulatory; private practice and university dermatology research centers. PATIENTS: Patients aged at least 18 years, with plaque psoriasis involving 10% or more of body surface area; 148 were screened and 112 were randomly assigned to treatment groups and received study drug. INTERVENTIONS: Patients received placebo or etanercept, 25 mg, subcutaneously twice a week for 24 weeks. Other psoriasis therapies were limited during the study. MAIN OUTCOME MEASURES: Safety measurements included tracking of adverse events and laboratory values. Efficacy was evaluated using the Psoriasis Area and Severity Index (PASI); the primary end point was a 75% improvement in PASI. Other efficacy measurements included patient and physician global assessments and quality-of-life measures. RESULTS: After 12 weeks of treatment, 17 (30%) of the 57 etanercept-treated patients and 1 (2%) of the 55 placebo-treated patients had achieved PASI 75%, and after 24 weeks, 32 (56%) of etanercept-treated patients and 3 (5%) of placebo-treated patients had reached this level (P<.001 for both time points). By 24 weeks, psoriasis was clear or minimal by physician's global assessment in more than 50% of patients who received etanercept. Treatment failure (PASI response <50) occurred in 23% of patients at week 24. All other measures confirmed the efficacy of etanercept. Adverse events were similar among etanercept and placebo groups. CONCLUSION: Etanercept monotherapy provided significant benefit to patients with psoriasis and had a favorable safety profile.

Efficacy and safety of calcipotriene 0.005% foam for the treatment of plaque-type psoriasis: results of two multicenter, randomized, double-blind, vehicle-controlled, phase III clinical trials.

BACKGROUND: Topical calcipotriene is frequently prescribed for the treatment of plaque-type psoriasis. Calcipotriene is currently available in the US as an ointment, a solution, a cream, and in a fixed-dose combination ointment with betamethasone dipropionate. Calcipotriene 0.005% has recently been formulated as a foam using a novel aqueous-based formulation to provide a new topical treatment option for patients with psoriasis. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of topical calcipotriene 0.005% foam for the treatment of mild to moderate plaque-type psoriasis. DESIGN: Two identical, randomized, double-blind, vehicle-controlled, 8-week phase III clinical trials. INTERVENTION: Subjects with plaque-type psoriasis affecting 2-20% of the body surface area, with an identifiable target lesion affecting the trunk or extremities, were randomized in a 2:1 ratio to calcipotriene foam (n = 437) or vehicle foam (n = 222). Study medication was applied twice daily for 8 weeks. OUTCOME MEASURES: Treatment success was defined as a score of 0 or 1 (clear or almost clear) on the Investigator's Static Global Assessment (ISGA) psoriasis rating scale and a minimum improvement of ISGA score of at least 2 grades from baseline. Predefined target lesions were assessed for erythema, scaling, and plaque thickness. Primary endpoint was the proportion of subjects in each treatment group who achieved treatment success after 8 weeks, analyzed on an intent-to-treat (ITT) basis. In the primary endpoint analysis, subjects missing 8-week outcomes data were classified as treatment failures regardless of their outcomes at earlier evaluations. As part of the sensitivity analysis, a last-observation-carried-forward (LOCF) approach to impute missing 8-week efficacy outcomes also examined treatment. Secondary endpoints included treatment success as a function of baseline ISGA score (mild or moderate), ISGA score of 0 or 1 (clear or almost clear), and effects of treatment on target lesion. Adverse events (AEs) were recorded throughout the study. RESULTS: In the ITT population of Study 1, treatment success after 8 weeks was achieved by 14% of subjects in the calcipotriene foam group versus 7% of subjects in the vehicle foam group (p = 0.058). In the LOCF analysis, treatment success was achieved by more subjects with calcipotriene foam than with vehicle foam (15% vs 7%; p = 0.034). In Study 2, treatment success was achieved by more subjects in the calcipotriene foam group for the primary endpoint (27% vs 16%; p = 0.016) and the LOCF analysis (28% vs 16%; p = 0.010). Subjects in the calcipotriene foam group exhibited better response rates than did the vehicle foam group for most of the secondary outcomes. Calcipotriene foam was safe with an overall incidence of AEs similar to those experienced in the vehicle foam group. Application-site reactions were noted in approximately 1-2% of subjects in each group. No AE was reported in more than 2% of subjects in the calcipotriene foam group. Treatment was discontinued because of AEs in approximately 2% of subjects in both groups. CONCLUSIONS: In two identically designed, phase III clinical trials, calcipotriene 0.005% foam was safe and effective for the treatment of mild to moderate plaque-type psoriasis for up to 8 weeks. CLINICAL TRIAL REGISTRATION: Registered at clinicaltrials.gov: NCT00688519 and NCT00689481.

Safety profile of intravenous and subcutaneous siplizumab, an anti-CD2 monoclonal antibody, for the treatment of plaque psoriasis: results of two randomized, double-blind, placebo-controlled studies.

Several biologics targeting different cytokines and receptors, including T-cell receptors, have been approved for psoriasis treatment. Siplizumab, a humanized anti-CD2 monoclonal antibody, may potentially provide an alternative therapy for psoriasis. Its safety profile and immunogenicity was examined in adults with plaque psoriasis. Two multicenter phase II randomized, double-blind, placebo-controlled studies: one tested two intravenous (I.V.) doses (0.012 and 0.04 mg/kg) of siplizumab every 2 weeks x 8 doses (124 patients); the second study tested three subcutaneous (S.C.) dose regimens of siplizumab (5 mg x 12 weeks, 5 mg x 6 weeks + placebo x 6 weeks, 7 mg x 4 weeks + placebo x 8 weeks), and placebo x 12 weeks (420 patients). Adverse events (AEs) and laboratory values were monitored. Immunogenicity was determined by anti-siplizumab antibodies quantification. In both studies, siplizumab exhibited an acceptable safety profile; most common AEs judged to be siplizumab related were lymphopenia, chills, and headache, reported at a higher frequency in the siplizumab-treated vs. placebo group. Siplizumab-related reductions in absolute lymphocyte count did not result in clinical evidence of immune suppression. Anti-siplizumab antibodies were detected after exposure to siplizumab; however, there was no evidence of an association between antibody development and AEs. Siplizumab exhibited an acceptable safety profile in adult patients with plaque psoriasis when administered as multiple I.V. or S.C. doses. Higher, clinically relevant doses of siplizumab would need to be tested to fully assess its safety.

Humanized anti-CD2 monoclonal antibody treatment of plaque psoriasis: efficacy and pharmacodynamic results of two randomized, double-blind, placebo-controlled studies of intravenous and subcutaneous siplizumab.

New biologic therapies focused primarily on cytokine pathways, some targeting T cell-mediated immune responses, are being developed for the treatment of psoriasis. Siplizumab is a humanized anti-CD2 monoclonal antibody that interferes with costimulation necessary for T cell activation and proliferation. We assessed the biological activity, serum concentrations, and pharmacodynamic effects of siplizumab in patients with plaque psoriasis. Two multicenter, phase II randomized, double-blind, placebo-controlled studies were conducted: one study randomized 124 patients to one of two intravenous (IV) doses (0.012 and 0.04 mg/kg) of siplizumab, given every 2 weeks x 8 doses; the other study randomized 420 patients to one of three subcutaneous (SC) dose regimens of siplizumab given weekly (5 mg for 12 weeks, 5 mg for 6 weeks, and 7 mg for 4 weeks) or placebo for 12 weeks. Adults with plaque psoriasis involving > or =10% of the body surface area and who were not receiving psoriasis therapy were eligible. Treatment with siplizumab resulted in reductions in psoriasis severity, but most of the effects were not statistically significant compared with placebo. Statistically significant differences among IV siplizumab-treated and placebo groups were observed at study day 28, with greater psoriasis area and severity index (PASI) score reductions from baseline in the siplizumab groups. The difference in PASI50 response rates between the 0.04 mg/kg siplizumab and placebo groups was also statistically significant at day 28. A trend toward clinical improvement was observed in SC siplizumab-treated groups. Significant reductions in circulating absolute lymphocyte counts and CD2+ (CD3+, CD8+, and CD16+/56+), but not CD2- (CD19+ and CD14+), lymphocyte populations were observed. These changes were not accompanied by concomitant reductions in infiltrating CD3+ lymphocytes in psoriatic lesions, epidermal thickness, or keratin 16 (K16) and intercellular adhesion molecule (ICAM) expression. The effect of siplizumab did not differentially affect CD45RO+ and CD45RA+ lymphocytes. Low or undetectable mean trough serum concentrations of siplizumab following IV or SC treatment were observed. Pharmacokinetic data coupled with higher-than-expected placebo clinical response rates may partly explain siplizumab's marginal clinical activity. Higher doses of siplizumab may be required to detect significant improvements in psoriasis; however, further development of this agent was not planned.

20th- to 21st-century technological challenges in soft coatings.

Coatings are among the most ancient technologies of humankind. Relatively soft coatings comprising organic materials such as blood, eggs, and extracts from plants were in use more than 20,000 years ago, and coating activity has been continuously practiced since then with gradually improving materials and application techniques. The fundamental purposes of protecting and/or decorating substrates have remained ubiquitous across all the centuries and cultures of civilization. This article attempts to extrapolate the long tale of change in soft coating technology from its current state by identifying some key problems that attract research and development efforts as our 21st century begins.