Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: Results from the SustaIMM phase 2/3 trial

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin‐23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/NCT03000075), a phase 2/3, double‐blinded, placebo‐controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross‐over to 75 mg risankizumab and placebo with cross‐over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross‐over to risankizumab at week 16. The primary end‐point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI‐90) at week 16 for risankizumab versus placebo. Missing data were imputed as non‐response. All primary and psoriasis‐related secondary end‐points were met for both risankizumab doses (P < 0.001). At week 16, PASI‐90 responses were significantly higher in patients receiving 75 mg (76%) or 150 mg (75%) risankizumab versus placebo (2%). Corresponding response rates were 86%, 93% and 10% for static Physician Global Assessment (sPGA) score of clear/almost clear; 90%, 95% and 9% for PASI‐75; and 22%, 33% and 0% for PASI‐100, with significantly higher responses for both risankizumab doses versus placebo. Through week 52, PASI and sPGA responses increased or were maintained and treatment‐emergent adverse events were comparable across treatment groups. Both doses of risankizumab were superior to placebo in treating patients with moderate to severe plaque psoriasis. The safety profile was consistent with previous risankizumab trials, with no new or unexpected safety findings.     

Efficacy and safety of Risankizumab in moderate to severe psoriasis: A systematic review and meta‐analysis

Monoclonal antibodies are explored for their therapeutic potential in Psoriasis. To evaluate Risankizumab in the moderate to severe psoriasis with regard to efficacy, tolerability, and safety PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltrials.gov , databases were searched for relevant RCTs. The reference lists of relevant publications were also scanned manually to identify any further studies not indexed in the searched databases. Only RCT aiming to evaluate the role of Risankizumab in the treatment of moderate to severe psoriasis were considered eligible for this systematic review. Intervention group was patients taking Risankizumab and placebo or other monoclonal antibody was considered as control group. Cochrane review manager 5 (RevMan) version 5.3 was used for data synthesis and meta‐analysis. Quality assessment of included randomized controlled trials was done with Cochrane Collaboration risk of bias assessment tool, version 2.0 (ROB‐2). Overall Grading of evidence for study objectives was performed with GRADE Pro GDT software. A total of seven studies were included in analysis with total of 1533 and 710 patients in Risankizumab and standard care groups, respectively. Statistically significant increase in percentage of individual achieving PASI90 (OR = 11.01 (95% CI = 8.67‐13.99), DLQI‐01 (OR = 6.95 (95% CI = 5.53‐8.75), sPGA‐01 (OR = 14.22 (95% CI = 11.10‐18.22); sPGA‐0 (OR = 6.39 (95% CI = 4.79‐8.54) in risankizumab group as compared with control, with high quality of evidence. Increased risk of infections with risankizumab as compared with placebo (OR = 1.44 [95% CI = 1.13‐1.83], high quality evidence), while no difference in SAE among two groups. Analysis of all outcome data from RCTs. In the light of evidence from systematic review on effectiveness of Risankizumab, we propose treatment with risankizumab for psoriasis patients not responding to available treatment.     

Is risankizumab better than secukinumab in the treatment of plaque psoriasis?

Plaque psoriasis is a common inflammatory disease that causes raised, flaky plaques or patches on the skin. An abnormal immune system can be an important cause of psoriasis. Risankizumab and secukinumab are biologic drugs that are injected under a patient’s skin to treat different parts of the immune system. Both drugs are approved in the U. S. and E. U. to treat moderate‐to‐severe plaque psoriasis. This international clinical study compared how well risankizumab and secukinumab treated moderate‐to‐severe plaque psoriasis (efficacy) and evaluated how safe these drugs were for patients to use. Risankizumab (150 mg) or secukinumab (300 mg) were given to 327 adult psoriasis patients. After 16 weeks of treatment, researchers saw that risankizumab was not worse than secukinumab (noninferior) in treating psoriasis: 73·8% of patients treated with risankizumab achieved at least 90% improvement in the severity of their disease compared with 65·6% of patients treated with secukinumab. After 52 weeks of treatment, researchers saw that risankizumab was more effective than secukinumab (superior) in treating psoriasis: 86·6% of patients treated with risankizumab achieved at least 90% improvement in the severity of their disease compared with 57·1% of patients treated with secukinumab. At the same time, more patients treated with risankizumab than those treated with secukinumab also achieved clear or almost clear skin. Patients in this study were able to take either drug without any unanticipated problems. Linked Article:   Warren et al. Br J Dermatol 2021; 184 :50–59 .     

Clear or almost clear skin improves the quality of life in patients with moderate‐to‐severe psoriasis: a systematic review and meta‐analysis

Psoriasis Area and Severity Index (PASI) 75 response is currently considered the gold standard for assessing treatment efficacy in moderate‐to‐severe psoriatic patients. PASI 90 response denotes better clinical improvement compared to PASI 75. Very few studies have assessed if a greater PASI clinical response is associated with greater improvements in Dermatology Life Quality Index (DLQI). A systematic review and meta‐analysis was performed to assess the association between PASI response and DLQI. The study was conducted to assess whether greater improvement in PASI scores from PASI 75–89 to PASI 90 is associated with greater Quality of life (QoL) improvements, specifically DLQI scores. Systematic searches were conducted in MEDLINE, EMBASE and Cochrane Library to identify studies evaluating biologic interventions in adult moderate‐to‐severe psoriasis patients reporting PASI response and their corresponding DLQI change from baseline score. The quality of evidence was assessed through Jadad score for randomized controlled trials and Downs and Black's checklist for observational studies. Meta‐analysis estimated change from baseline in DLQI for PASI 75–89 responders to be 78% (95% credible intervals [CrI]: 75–82%) and for PASI 90 responders to be 90% (95% CrI: 88–93%). This implies 12% greater improvement in DLQI score for PASI 90 responders compared with PASI 75–89 responders. In addition, the meta‐analysis also showed a statistically significant difference in DLQI score of 0/1 between PASI 75‐89 and PASI 90 responders (45% [95% Crl]; 41.0–50.0% and 73% [95% Crl]; 70.0–76.0%), respectively, Bayesian P < 0.0001). In conclusion, substantial improvement in clinical efficacy is associated with improved QoL in patients with moderate‐to‐severe psoriasis suggesting that PASI 90 responders (clear or almost clear skin) could achieve a superior QoL compared to PASI 75–89 responders.     

Efficacy and safety of tofacitinib for moderate‐to‐severe plaque psoriasis: a systematic review and meta‐analysis of randomized controlled trials

The effects of tofacitinib in treating moderate‐to‐severe plaque psoriasis were unclear. We aimed to assess the effects of tofacitinib in treating moderate‐to‐severe plaque psoriasis. We searched PubMed, Cochrane Central Register of Controlled Trials and EMBASE for relevant randomized controlled trials (RCTs) and conducted a systematic review and meta‐analysis. Four RCTs with 2724 participants were included. Compared to placebo, tofacitinib significantly improved psoriasis {≥75% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: risk difference (RD) 0.32 [95% confidence interval (CI) 0.28–0.35], 10 mg BID: RD 0.51 (95% CI 0.43–0.58); ≥90% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: RD 0.19 (95% CI 0.17–0.22), 10 mg BID: RD 0.36 (95% CI 0.31–0.42); Physician's Global Assessment 0/1: 5 mg BID: RD 0.31 (95% CI 0.27–0.35), 10 mg BID: RD 0.48 (95% CI 0.44–0.53)} and participants’ life quality [Dermatology Life Quality Index 0/1: 5 mg BID: RD 0.24 (95% CI 0.20–0.2), 10 mg BID: RD 0.36 (95% CI 0.33–0.40)]. Tofacitinib was associated with an increase in minor adverse events [upper respiratory tract infection: 5 mg BID: RD 0.02 (95% CI 0.00–0.03), 10 mg BID: RD 0.02 (95% CI 0.00–0.04); hypercholesterolaemia: 5 mg BID: RD 0.02 (95% CI 0.01–0.04), 10 mg BID: RD 0.02 (95% CI 0.01–0.04)]. In conclusion, tofacitinib may be a treatment option for moderate‐to‐severe plaque psoriasis that is unresponsive to other therapies and patients who are intolerable to other therapies or prefer oral medications.     

Ustekinumab improves health-related quality of life in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial

Background PHOENIX 1 was a phase III, randomized, double‐blind, placebo‐controlled study that demonstrated the long‐term efficacy and safety of ustekinumab in patients with moderate‐to‐severe psoriasis. Objectives To assess the effect of ustekinumab maintenance therapy on health‐related quality of life (HRQoL) in PHOENIX 1 patients. Patients and methods Patients (n = 766) were randomized to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and every 12 weeks thereafter, or placebo (n = 255) at weeks 0 and 4 with crossover to ustekinumab at week 12. Ustekinumab‐randomized patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI) 75 at weeks 28 and 40 were re‐randomized at week 40 to continue ustekinumab or be withdrawn until loss of therapeutic effect. HRQoL was assessed using the SF‐36 and Dermatology Life Quality Index (DLQI). Results At baseline, more than 97% had a DLQI > 1 and the average DLQI was > 10, indicating a significant impact on patients’ HRQoL. Significantly greater proportions of patients receiving ustekinumab 45 and 90 mg achieved a normalized DLQI score (≤ 1) compared with placebo (53·2%, 52·4% and 6·0%, respectively, both P < 0·001) at week 12 and achieved a clinically meaningful improvement (increase of at least five points) in SF‐36 physical (23·1%, 33·7% and 15·6%) and mental (25·5%, 31·3% and 14·8%) component summary scores. At week 12, changes in individual DLQI and SF‐36 domains were significantly better in each ustekinumab group vs. placebo (P < 0·001). The magnitude of improvement across SF‐36 scales was greatest for the bodily pain and social functioning domains. Improvements in HRQoL were sustained with maintenance ustekinumab therapy through at least 1 year. Regression analysis showed that, after adjustment for improvement in PASI or Physician’s Global Assessment (PGA), ustekinumab‐treated patients demonstrated significant improvements in DLQI. Conclusions Ustekinumab improves HRQoL in patients with moderate‐to‐severe psoriasis. Patient‐reported outcomes measured a treatment effect beyond that indicated by clinical measures.     

Efficacy and safety of systemic treatments for moderate‐to‐severe psoriasis: meta‐analysis of randomized controlled trials

Dermatologists may choose from various conventional and biological systemic agents to treat patients with moderate‐to‐severe psoriasis. We set out to analyse systematically the efficacy and tolerability of approved treatments for moderate‐to‐severe psoriasis. We undertook a systematic review and meta‐analysis of randomized controlled trials (RCTs) investigating the efficacy of systemic treatment approved for moderate‐to‐severe psoriasis. Efficacy was assessed as the proportion of participants with 75% improvement in Psoriasis Area and Severity Index at primary efficacy measurement (week 8–16). Safety was summarized as rates of adverse events and withdrawals. Direct and indirect comparative efficacy was assessed by random effects meta‐analysis of risk differences (RDs). In total, 48 eligible RCTs totalling 16 696 patients (11 178 randomized to biologics, 1888 to conventional treatments) were identified. In placebo‐controlled trials, infliximab was the most efficacious [RD 76%, 95% confidence interval (CI) 73–79%]. Adalimumab (RD 61%, 95% CI 56–67%), and ustekinumab 45 mg (RD 63%, 95% CI 59–66%) and 90 mg (RD 67%, 95% CI 60–74%) each had similar efficacy. These biologics are more effective than etanercept and all conventional treatments. Head‐to‐head trials indicate the superiority of adalimumab and infliximab over methotrexate (MTX), the superiority of ustekinumab over etanercept, the nonsignificant superiority of ciclosporin over MTX, and the dose‐dependent efficacy of etanercept and ustekinumab. Fumaric acid is as efficacious as MTX. Safety of treatments could not be pooled due to a lack of standardization in reporting across trials. In conclusion, the qualitative and quantitative evidence is much stronger for biological interventions than for conventional treatments.     

Efficacy of systemic therapies for moderate‐to‐severe psoriasis: a systematic review and meta‐analysis of long‐term treatment

Background Despite the chronicity of psoriasis, most systematic reviews focus on short‐term treatment. Methods The systematic search strategy and results from the German Psoriasis Guidelines were adapted. To update the data a literature search in Medline, Embase and the Cochrane Library was conducted. The proportion of participants achieving ≥75% decrease in Psoriasis Area and Severity Index (PASI) as well as Dermatology Life Quality Index (DLQI) reduction at different time points were assessed. Trials were summarized with respect to time periods and study designs. Suitable trials were included in a meta‐analysis. Particular attention was paid to statistical approaches of handling dropouts. Results A total of 33 articles including 27 trials totaling 6575 patients with active treatment were included in the systematic review. Seven randomized controlled trials were eligible for the meta‐analysis. Over a 24 week treatment period infliximab [risk difference (RD) 78%, 95% confidence interval (CI) 72–83%] and ustekinumab 90 mg every 12 weeks (RD 77%, 95% CI 71–83%) were the most efficacious treatments. Adalimumab (RD: 60%, 95% CI 45–74%) showed results within the range of different etanercept dosages (etanercept 50 mg once weekly: RD 62%, 95% CI, 52–72%), (etanercept 25 mg twice weekly: RD 45%, 95% CI 34–56%), (etanercept 50 mg twice weekly: RD 56%, 95% CI 49–62%) and (etanercept 50 mg twice weekly until week 12, then 25 mg twice weekly: RD 50%, 95% CI 42–57%). After 24 weeks a decrease in efficacy for inflximab, adalimumab and etanercept was observed. Conclusions More sufficient data is required to draw reliable conclusions in extended long‐term treatment and head‐to‐head comparisons are necessary.     

Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years

Background An unmet need remains for safe and effective long‐term treatments of psoriasis. Objectives To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial. Methods Patients (n = 766) with moderate‐to‐severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re‐randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50–74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician’s Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures. Results Overall, 79·8% of the ustekinumab‐treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. Conclusions Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.     

Five‐year experience with infliximab: Follow up of the product familiarisation program

This 5‐year retrospective analysis is of 22 patients who participated in the product familiarisation program (PFP) at St Vincent's Hospital Melbourne, prior to the listing of infliximab on the Pharmaceutical Benefit Scheme. Criteria for inclusion were being an adult with chronic plaque psoriasis, having a psoriasis area and severity index (PASI) score of at least 15 with an inadequate response or intolerance to three of the following: phototherapy, acitretin, cyclosporin and methotrexate. Participants were infused with infliximab 5 mg/kg on the standard induction (weeks 0, 2 and 6) and maintenance (8‐weekly) protocols. At each visit PASI and dermatology life quality index (DLQI) scores were recorded. Success was determined as the proportion of patients achieving at least a 75% improvement in the PASI score from baseline (PASI 75). At 60 months after commencement of therapy, 31% of patients remained on infliximab. Those who did retained PASI 75 with a DLQI of 0 or 1. Of those who ceased infliximab, nine did so due to loss of efficacy, three for personal reasons, two for serious adverse events and one was lost to follow up. Adverse events included non‐melanoma skin cancers, infections and abnormal liver enzymes. Infliximab in the Australian context has proven to be a highly effective treatment of chronic plaque psoriasis, and patients who remained on the drug derived a high level of satisfaction, assessed both subjectively (DLQI) and objectively (PASI 75). The variable response indicates that psoriasis is a heterogeneous disease and investigation into potential patient selection for treatment in the future is warranted.     

Effectiveness of anti‐interleukin 23 biologic drugs in psoriasis patients who failed anti‐interleukin 17 regimens. A real‐life experience

Among the most recent biologic drugs available for psoriasis therapy, those targeting interleukin‐17 (secukinumab and ixekizumab) or its receptor (brodalumab) have been shown to be quickly effective. However, in those patients who failed one or more of the above‐cited drugs, real‐life data on the effectiveness of switching to one anti‐interleukin‐23 biologic (guselkumab, risankizumab, or tildrakizumab) are very scarce. Here, we report our experience in treating 12 multi‐failure psoriatic patients, prospectively followed‐up over 6 months, who showed a significant improvement in their psoriasis after switching from an anti‐interleukn‐17 to an anti‐interleukin‐23 drug.     

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.     

Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Psoriasis is a chronic disease that requires long‐term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)‐23. This article reviews published data on the safety of these IL‐23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo‐ and active‐controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk–benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL‐23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL‐23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long‐term extension studies and patient registries will further establish the safety profile of IL‐23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.     

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.     

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 demonstrates high sustained efficacy and a favourable safety profile in patients with moderate‐to‐severe psoriasis through 5 years of treatment (SCULPTURE Extension Study)

Background

Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL‐17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate‐to‐severe psoriasis and psoriatic arthritis.

Objective

To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate‐to‐severe psoriasis.

Methods

In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double‐blinded until the end of Year 3 and open‐label from Year 4. Here, we focus on the 300 mg fixed‐interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses.

Results

At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified.

Conclusion

Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate‐to‐severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.     

Review of phase III trial data on IL‐23 inhibitors tildrakizumab and guselkumab for psoriasis

The development of monoclonal antibodies targeting IL‐12 and IL‐23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL‐23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti‐IL‐23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti‐IL‐23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti‐IL‐23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL‐17 inhibitors with a favourable short‐term safety profile. The results of the phase III trials support the notion that IL‐23 is a potential target in psoriasis treatment.     

Secukinumab efficacy and safety in Japanese patients with moderate‐to‐severe plaque psoriasis: Subanalysis from ERASURE,a randomized,placebo‐controlled,phase 3 study

Secukinumab, a fully human anti‐IL‐17A monoclonal antibody, neutralizes IL‐17A, a key cytokine in the pathogenesis of psoriasis. Efficacy and safety of secukinumab was evaluated in Japanese patients with moderate‐to‐severe plaque psoriasis as part of a large Phase 3 global study (ERASURE). In this 52‐week, double‐blind study (ClinicalTrials.gov Identifier: NCT01365455, JapicCTI‐111529), 87 patients from Japan (11.8% of 738 patients randomized in the overall study population) were equally randomized to receive secukinumab 300 mg or 150 mg, or placebo once weekly at baseline and at Weeks 1, 2, 3 and 4, then every 4 weeks. Co‐primary endpoints (Week 12) were ≥75% improvement in psoriasis area‐and‐severity index (PASI 75) from baseline and a score of 0 (clear) or 1 (almost clear) on a 5‐point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo. PASI 75 and IGA mod 2011 0/1 responses at Week 12 were superior with secukinumab 300 mg (82.8% and 55.2%, respectively) or 150 mg (86.2% and 55.2%, respectively) versus placebo (6.9% and 3.4%, respectively; P < 0.0001 for all). Greater than 90% improvement in PASI (PASI 90) was also superior with secukinumab 300 mg (62.1%) or 150 mg (55.2%) versus placebo (0.0%) at Week 12 (P < 0.0001 for both). Clinical responses were sustained up to Week 52 in the majority of patients. During a 12‐week induction period, adverse event incidences were 48.3% with secukinumab 300 mg, 55.2% with 150 mg, and 41.4% with placebo. Secukinumab showed robust and sustainable efficacy in symptom reduction for moderate‐to‐severe plaque psoriasis in the Japanese patients.     

PASI90 response: the new standard in therapeutic efficacy for psoriasis

In a non‐life‐threatening disease such as psoriasis, treatment goals should be referred to the improvement in severity and extent of the disease and their impact on patients’ perceived health‐related quality of life (HRQoL), usually measured by the Dermatology Life Quality Index (DLQI). The ultimate goal of therapy is blanching, and an improvement of 90% or better (PASI90 response) with respect to baseline Psoriasis Area and Severity Index (PASI) is considered as treatment success by the European Medicines Agency. PASI75 response has become accepted as a less stringent reasonable therapeutic goal, but absolute PASI values might provide a better benchmark, irrespective of baseline PASI. Anyway, objective measures of psoriasis involvement are clinically meaningful only if they correlate with significant improvements in DLQI, and especially with the achievement of a DLQI = 0–1 status, corresponding to lack of effect of the disease on patient's HRQoL. Even though PASI75 response meets therapeutic expectations in most patients, PASI90 response or better has a significantly higher impact on DLQI improvement and is associated with significantly higher DLQI = 0–1 response rates. The introduction of anti‐IL17 drugs in clinical practice bears the promise of achieving PASI90 response or better in the majority of patients, and initial data suggest that the PASI90 benchmark provides better discriminatory value as regards achievement of DLQI = 0–1 response. Further research is required to confirm the value of absolute PASI cut‐offs as a measure of therapeutic success independent of baseline and duration of treatment, and to develop newer, more practical and more accurate measures of psoriasis severity.     

Long‐term efficacy of ustekinumab in patients with moderate‐to‐severe psoriasis treated for up to 5 years in the PHOENIX 1 study

Background Ongoing evaluation of biological agents in patients with moderate‐to‐severe psoriasis is needed to support their long‐term use. Objective To evaluate long‐term efficacy and safety of ustekinumab through 5 years in the PHOENIX 1 study. Methods Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every‐12‐weeks thereafter; placebo patients crossed‐over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders [Weeks 28/40] re‐randomized at Week 40 to continue every‐12‐week maintenance) and Partial Responders (i.e. <PASI 75 responders adjusted to every‐8‐week maintenance at Weeks 28 or 40). Safety endpoints were evaluated through Week 264 for the Overall Population. Results  Overall, 68.7% (517/753) of ustekinumab‐treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders [79.1% (45 mg) and 80.8% (90 mg)] and Partial Responders [57.6% (45 mg) and 55.1% (90 mg)]. With 3104 patient‐years of follow‐up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses. Conclusions Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.