Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II,multicenter, randomized,double‐blind,placebo‐controlled,parallel‐group,dose‐comparison study

Background Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro‐inflammatory and anti‐inflammatory mediator production. Objective Assess apremilast efficacy and safety in moderate to severe plaque psoriasis. Methods Phase II, 12‐week, multicenter, double‐blind, placebo‐controlled, parallel‐group, dose‐comparison study of 259 subjects randomized 1 : 1 : 1 to placebo, apremilast 20 mg QD or apremilast 20 mg BID. Results More subjects receiving apremilast 20 mg BID achieved ≥ 75% reduction in Psoriasis Area and Severity Index (PASI‐75) vs. placebo (24.4% vs. 10.3%; P = 0.023). A similar proportion of subjects receiving apremilast 20 mg QD and placebo achieved PASI‐75 at week 12 [9/87 (10.3%, each group)]. Mean per cent reduction in PASI from baseline was 17.4% for placebo, 30.3% for apremilast 20 mg QD (P = 0.021 vs. placebo) and 52.1% for apremilast 20 mg BID (P < 0.001). Apremilast 20 mg BID significantly decreased mean body surface area involvement vs. placebo (30.8% vs. 3.2%; P < 0.001). The most common adverse events were headache, nasopharyngitis, diarrhoea and nausea. Most events (> 90%) were mild to moderate and did not lead to study discontinuation. Serious adverse events occurred in four placebo subjects (panic attack, hospitalization for rehabilitation, hospitalization for alcoholism, worsening psoriasis), one receiving apremilast 20 mg QD (knee surgery) and in one receiving apremilast 20 mg BID (worsening psoriasis). The panic attack was considered treatment‐related; both cases of worsening psoriasis occurred after medication discontinuation. No deaths or opportunistic infections were reported. Conclusion Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis.     

Treatment of palmoplantar psoriasis with infliximab: a randomized,double‐blind placebo‐controlled study

Background Palmoplantar psoriasis is a difficult to treat variant of plaque psoriasis. Objective To study the safety and efficacy of infliximab in non‐pustular palmoplantar psoriasis. Methods Patients with non‐pustular palmoplantar psoriasis affecting at least 10% of their palms and soles and with a modified palmoplantar psoriasis area and severity index (m‐PPPASI) of at least eight were recruited. Patients were randomized (1:1) to receive infliximab 5 mg/kg or placebo at weeks 0, 2 and 6. Patients initially randomized to placebo received infliximab at weeks 14, 16 and 20 whereas patients randomized to infliximab received additional infliximab infusions every 8 weeks until week 22. Results Twenty four (24) patients were randomized in this study. At week 14, 33.3% and 66.7% of patients treated with infliximab achieved m‐PPPASI 75 and m‐PPPASI 50 respectively compared to 8.3% for both m‐PPPASI 75 (P = 0.317) and m‐PPPASI 50 (P = 0.009) for patients randomized to placebo. A reduction of 50.3% in the mean surface area of palms and soles affected with psoriasis was seen at week 14 in patients randomized to infliximab as compared to an increase of 14.9% in patients randomized to placebo (P = 0.009). Conclusions This pilot study did not reach its primary endpoint of m‐PPPASI 75 at week 14. However, infliximab was observed to be more efficacious than placebo in improving PPSA and with respect to the percentage of patients reaching m‐PPPASI 50 at week 14. Larger and longer term studies are needed for severe patients to better assess the efficacy of infliximab in palmoplantar psoriasis.     

Guselkumab,an anti‐interleukin‐23 monoclonal antibody,for the treatment of moderate to severe plaque‐type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized,double‐blind,placebo‐controlled study

Previous global studies of guselkumab have demonstrated clinical benefits in patients with psoriasis. The aim of this 52‐week, phase 3 study was to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque‐type psoriasis. Patients randomly received guselkumab 50 mg or 100 mg at weeks 0, 4 and every 8 weeks, or placebo with cross‐over to guselkumab 50 mg or 100 mg at week 16. Co‐primary end‐points were the proportion of patients achieving Investigator's Global Assessment (IGA) cleared/minimal (0/1) and 90% or more improvement in Psoriasis Area and Severity Index (PASI‐90) at week 16. Overall, 192 patients were randomized to placebo, guselkumab 50 mg or 100 mg. At week 16, patients in the placebo group were crossed over to guselkumab 50 mg or 100 mg. At week 16, a significantly (P < 0.001) higher proportion of patients receiving guselkumab 50 mg and 100 mg versus placebo achieved IGA 0/1 (92.3% and 88.9% vs 7.8%) and PASI‐90 (70.8% and 69.8% vs 0%). Patients in guselkumab 50 mg and 100 mg groups achieved significant improvement versus placebo in PASI‐75 (89.2% and 84.1% vs 6.3%, P < 0.001) at week 16; improvement was maintained through week 52. Incidences of treatment‐emergent adverse events were comparable among the groups through week 16; the most commonly reported was nasopharyngitis. No new safety concerns were observed until week 52. In conclusion, guselkumab treatment demonstrated superior efficacy over placebo and was well tolerated in Japanese patients with moderate to severe plaque‐type psoriasis.     

Efficacy and safety of secukinumab in the treatment of moderate‐to‐severe plaque psoriasis: a randomized,double‐blind,placebo‐controlled phase II dose‐ranging study

Background Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long‐term safety. Interleukin (IL)‐17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. Objectives To assess the efficacy and safety of different doses of secukinumab, a fully human anti‐IL‐17A IgG1κ monoclonal antibody, in patients with moderate‐to‐severe plaque psoriasis. Methods Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12‐week treatment period, patients entered a follow‐up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates. Results After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow‐up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow‐up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort. Conclusions Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate‐to‐severe psoriasis.     

Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized,double‐blind,phase III NAVIGATE trial

Psoriasis is a chronic disease causing red and scaling skin lesions. Current treatments, especially biologics, which are either given by injection or intravenous infusion (IV), are very effective in the treatment of moderate to severe plaque psoriasis. However, most patients look to achieve clear skin, so there is room for improvement. One approved biologic, ustekinumab, blocks two of the body's internal proteins, interleukin (IL)‐12 and IL‐23. Blocking these proteins prevents signals that cause inflammation in psoriasis. While ustekinumab is effective in many patients, most will not achieve complete skin clearance. Because recent scientific evidence shows that IL‐23 may be more important than IL‐12 in causing psoriasis, guselkumab, a new treatment that specifically targets IL‐23, but not IL‐12, has been developed and was recently approved in the U.S. to treat moderate to severe psoriasis. In the NAVIGATE trial, 871 patients with moderate‐to‐severe plaque psoriasis received ustekinumab and if, after 16 weeks, patients were not clear or almost clear, they were randomly assigned to either continue ustekinumab or start treatment with guselkumab until week 44. From week 16 until week 40, the average number of visits (maximum = 4) at which patients were clear or almost clear was significantly greater in patients treated with guselkumab (1.5) than with ustekinumab (0.7). In addition, at week 28, twice the proportion of patients on guselkumab (31.1%) were clear or almost clear than on ustekinumab (14.3%). Infections were the most commonly reported adverse event among patients on either guselkumab or ustekinumab. The authors conclude that for patients who do not achieve clear or almost clear skin after ustekinumab treatment, switching to guselkumab could be an effective treatment strategy and did not raise safety concerns.     

A randomized,double‐blind,placebo‐controlled trial to determine the efficacy and safety of lactoferrin with vitamin E and zinc as an oral therapy for mild to moderate acne vulgaris

Lactoferrin is an iron‐binding milk‐derived protein that has shown antibacterial and anti‐inflammatory effects in vitro and in vivo. The objective of this study was to determine the efficacy and safety of lactoferrin, combined with vitamin E and zinc, for mild to moderate acne vulgaris. In this randomized, double‐blind, placebo‐controlled trial, 168 subjects aged 13–40 years old were randomly assigned to take either a capsule formulation containing lactoferrin with vitamin E and zinc or placebo twice a day for 3 months. The primary outcome measure was a reduction in the number of acne lesions compared to placebo. A total of 164 subjects completed the study per protocol. The lactoferrin group (n = 82) showed a significant median percent reduction in total lesions as early as 2 weeks (14.5%, P = 0.0120), with the maximum reduction occurring at week 10 (28.5%, P < 0.0001) compared to placebo group (n = 82). Maximum reduction in comedones (32.5%, P < 0.0001) and inflammatory lesions (44%, P < 0.0001) was also seen at week 10 compared to placebo. Sebum scores were improved by week 12. No adverse events were observed during the trial. A twice daily regimen of lactoferrin with vitamin E and zinc significantly reduced acne lesions in people with mild to moderate acne vulgaris.     

Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial

Background There is a need for the development of novel nonsteroidal topical drugs for the treatment of atopic dermatitis (AD). Objectives The primary objective was to evaluate the efficacy of WBI‐1001 over 6 weeks of treatment of mild to severe AD. Methods Patients with AD affecting 3–20% of their body surface area and with an Investigator’s Global Assessment (IGA) of 2–4 were randomized (1 : 1 : 1) to receive placebo, WBI‐1001 0·5% or WBI‐1001 1·0% in a cream formulation applied twice daily for 6 weeks. At the end of this phase, patients receiving WBI‐1001 continued the same treatment for an additional 6 weeks. Patients receiving placebo entered into a 6‐week double‐blind phase with re‐randomization (1 : 1) to WBI‐1001 0·5% or 1·0% cream. The primary objective was to evaluate the efficacy of WBI‐1001 over 6 weeks of treatment of mild to severe AD. The primary endpoint was the mean change from baseline in IGA at day 42 (week 6). Results In total, 148 patients were randomized and analysed in the placebo (51), WBI‐1001 0·5% (50) and WBI‐1001 1·0% (47) groups. There was a decrease of 1·3 [43%; P < 0·001; 95% confidence interval (CI) ?1·2 to ?0·5] and 1·8 (56·3%; P < 0·001; 95% CI ?1·6 to ?0·9) in IGA at day 42 in the WBI‐1001 0·5% and 1·0% groups, respectively, as compared with a decrease of 0·5 (14·7%) in the placebo group. Adverse drug reactions included a few cases of folliculitis and contact dermatitis. Conclusions WBI‐1001 is an efficacious novel topical anti‐inflammatory molecule for the treatment of AD.     

Efficacy,safety and tolerability of topical terbinafine nail solution in patients with mild‐to‐moderate toenail onychomycosis: results from three randomized studies using double‐blind vehicle‐controlled and open‐label active‐controlled designs

Background Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. Objective To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. Methods Subjects with mild‐to‐moderate toe onychomycosis (25% to ≤75% nail‐involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double‐blind studies, and to TNS or amorolfine in an active‐controlled, open‐label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual‐involvement and negative mycology) at week 52. Results Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well‐tolerated. Conclusion Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.     

Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized,placebo‐controlled phase 3 trial

Tofacitinib is an oral Janus kinase inhibitor. These post‐hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52‐week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo‐treated patients advanced to tofacitinib at week 16. Primary efficacy end‐points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI‐75) and Physician's Global Assessment (PGA) of “clear” or “almost clear” (PGA response) at week 16. Other end‐points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI‐75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.     

Secukinumab induction and maintenance therapy in moderate‐to‐severe plaque psoriasis: a randomized,double‐blind,placebo‐controlled,phase II regimen‐finding study

Background Interleukin (IL)‐17A has major proinflammatory activity in psoriatic lesional skin. Objectives To assess the efficacy and safety of secukinumab, a fully human IgG1κ monoclonal anti‐IL‐17A antibody, in moderate‐to‐severe plaque psoriasis in a phase II regimen‐finding study. Methods A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed‐interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment‐at‐start‐of‐relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). Results At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54·5% and 42·0% vs. 1·5%; P < 0·001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed‐interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start‐of‐relapse regimen [67% (n = 45), P = 0·020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed‐interval and start‐of‐relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection‐site reactions were reported. Reported cases of neutropenia were mild‐to‐moderate (≤ grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long‐term safety. Conclusions Secukinumab shows efficacy for induction and maintenance treatment of moderate‐to‐severe plaque psoriasis.