Association of disease duration and PASI response rates at week 12 in patients with moderate-to-severe plaque psoriasis receiving biologics in the real-world psoriasis study of health outcomes (PSoHO).

PURPOSE: Currently, in the treatment of moderate-to-severe psoriasis (PsO) there is a lack of evidence demonstrating optimal biologic treatment response with respect to disease duration. The aim of this post-hoc analysis, using real world data from the Psoriasis Study of Health Outcomes (PSoHO), is to provide evidence if early intervention with biologics is associated with better treatment outcomes and if there is any difference among drug classes or individual biologics. MATERIALS AND METHODS: For this post-hoc analysis patients were categorised into two subgroups according to shorter (≤2 years) or longer (>2 years) disease duration. Analysis was performed on anti-interleukin (IL)-17A cohort vs other biologics cohort, anti-IL-17A vs other drug classes, and pairwise comparisons of ixekizumab vs individual biologics, provided that the statistical models converged. Analysis investigated the association of disease duration with the proportion of patients achieving 100% improvement in Psoriasis Area Severity Index score (PASI 100) at week 12. Adjusted comparative analyses, reported as odds ratio (OR), were performed using Frequentist Model Averaging (FMA) for each cohort or treatments within each subcategory of the subgroups. RESULTS: At week 12, anti-IL-17A and other biologics cohorts displayed minimal differences in numerical response rate for PASI 100 with respect to disease duration. The anti-IL-17A cohort showed a higher numerical PASI 100 response rate compared to the other biologic cohort irrespective of disease duration (≤2 years: 36.7% vs 21.8%; >2 years: 35.8% vs 21.9%). CONCLUSION: Overall, the results do not clearly indicate that treating patients early is critical in achieving optimal patient outcomes. Furthermore, patients treated with ixekizumab show numerically higher response rates relative to other individual biologics irrespective of disease duration.

Outcomes for Psoriasis by Self-Identified Racial Groups in Ixekizumab Clinical Trials: A Pooled Analysis.

BACKGROUND: Biologics have shown promising outcomes in psoriasis clinical trials. However, there is a paucity of data exploring the potential differences in outcomes between self-identified racial groups. OBJECTIVE: To evaluate treatment response to ixekizumab in patients with psoriasis across different self-identified racial subgroups. METHODS: This study analyzed pooled data from 5 clinical studies (UNCOVER-1, UNCOVER-2, UNCOVER-3, IXORA-R, and IXORA-S) with patients of different self-identified racial subgroups, who were treated with an on-label dose of ixekizumab for psoriasis through 12 weeks. Treatment response to ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI) and static Physician’s Global Assessment response rates. Patient Global Assessment of Disease Severity, Itch Numeric Rating Scale, Skin Pain Visual Analog Scale, and Dermatology Life Quality Index were used to evaluate the patient-reported outcomes (PROs) and impact on quality of life (QoL). RESULTS: A total of 1825 ixekizumab-treated patients from 5 pooled studies were included. Consistent with the clinical outcomes from the overall population, all self-identified racial groups showed rapid improvement in PASI through Week 12, although the response was somewhat slower in American Indian/Alaska Native patients. Differences in PROs and QoL assessments were observed among racial groups, especially in patients who identified as Black/African American and American Indian/Alaska Native. CONCLUSION: Ixekizumab is effective through 12 weeks of treatment for psoriasis across different self-identified racial groups. Sample sizes for some racial groups were small (N≤12), therefore, further research is required to understand potential differences in psoriasis treatment with ixekizumab between various racial groups.J Drugs Dermatol. 2024;23(2):17-22.  doi:10.36849/JDD.7672.

Speed and Cumulative Responses According to Body Regions in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Ixekizumab (Interleukin-17A Antagonist) versus Guselkumab (Interleukin-23p19 Inhibitor).

INTRODUCTION: When assessing the effect of a therapy for psoriasis (PsO), it is important to consider speed of response and cumulative response. However, responses among biologics may differ by body regions. This post hoc analysis compares speed of response and cumulative response for ixekizumab (IXE), an interleukin-17A antagonist, and guselkumab (GUS), an interleukin-23p19 inhibitor, in different body regions of patients with moderate-to-severe plaque PsO participating in the IXORA-R study, up to week 24. METHODS: The IXORA-R design has been previously described. Patients received the respective on-label dosing of IXE or GUS. The median time to first Psoriasis Area and Severity Index (PASI) 50, 75, 90, and 100 response (50%, 75%, 90%, and 100% improvement from baseline, respectively) and the cumulative days with clear skin for PASI 50, 75, 90, and 100 responses were assessed in four body regions: head, trunk, upper extremities, and lower extremities. RESULTS: A total of 1027 patients were enrolled and received IXE (N = 520) or GUS (N = 507). Median time to first PASI 50, 75, 90, and 100 response was shortest in the head region, followed by the remaining body regions in both IXE and GUS cohorts. In each body region, IXE was significantly faster than GUS (p < 0.001) in achieving PASI 50, 75, 90, and 100. Through 24 weeks, the number of days with clear skin for PASI 90 and 100 was greater in the head region, followed by trunk, upper extremities, and lastly lower extremities in both IXE and GUS cohorts. In each body region, through 24 weeks, patients on IXE experienced a significantly higher number of days with clear skin for PASI 50, 75, 90, and 100 than patients on GUS (p < 0.01). CONCLUSIONS: As compared to GUS, IXE provided a faster skin clearance and more days with clear skin in all body regions of patients with moderate-to-severe plaque PsO through 24 weeks. TRIAL REGISTRATION NUMBER: https://www. CLINICALTRIALS: gov/ : NCT03573323 (IXORA-R).

Psoriasis, a long-term, inflammatory skin disease, impacts patient's lives, and response to treatment varies depending on the body region affected. Here, we assessed the speed of response and cumulative response through 24 weeks in different body regions (head, trunk, upper extremities, and lower extremities) of patients with moderate-to-severe plaque psoriasis treated with currently approved therapies: ixekizumab (IXE), an interleukin-17A antagonist, or guselkumab (GUS), an interleukin-23p19 inhibitor. We calculated the speed of response as the number of weeks to achieve first skin clearance, based on the Psoriasis Area and Severity Index (PASI) tool, and the cumulative response as the number of days with clear skin throughout the 24-week period. We found that the head region achieved skin clearance fastest and had a higher number of days with clear skin compared to the trunk, upper extremities, and lower extremities, in both groups of patients treated with IXE or GUS. Compared to GUS, IXE provided faster skin clearance and a higher number of days with clear skin in all body regions. For example, the head region of patients treated with IXE, as compared to GUS, achieved complete skin clearance twofold faster and experienced 18.7% more days of complete skin clearance. In conclusion, treatment with IXE through 24 weeks provided a faster response and a higher cumulative response than treatment with GUS in all four body regions of patients with moderate-to-severe plaque psoriasis.

Network meta-analyses comparing the efficacy of biologic treatments for achieving complete resolution of nail psoriasis at 24-28 and 48-52 weeks.

BACKGROUND: Available network meta-analyses (NMAs) comparing the efficacy of biologics in nail psoriasis (NP) have not included recently approved biologics such as bimekizumab nor have they provided comparisons up to 1 year. OBJECTIVE: We conducted two NMAs that update and extend results from a previous NMA comparing biologics for achieving complete resolution of NP. METHODS: Bayesian NMAs were performed using a generalized linear model with a logit link to model the binary outcome of nail clearance at weeks 24-28 and 48-52. RESULTS: For the NMA at weeks 24-28, which included seven biologics and placebo, the absolute probability of achieving complete resolution of NP was highest for ixekizumab (46.4%; 95% credibility interval [CrI] 35.2-58.0), followed by brodalumab (37.1%; 95% CrI 17.1-62.2) and bimekizumab (30.3%; 95% CrI 12.7-53.9). For the NMA at weeks 48-52, which included six biologics, the absolute probability was highest for ixekizumab (77.2%; 95% CrI 51.1-93.4), followed by adalimumab (75.6%; 95% CrI 61.5-87.3) and brodalumab (71.9%; 95% CrI 38.4-93.2). CONCLUSION: Among biologics included in these two NMAs, ixekizumab has the highest absolute probability of achieving complete resolution of NP. Results may help to inform treatment decisions for patients with NP.

Long-term Efficacy and Safety of Up to 108 Weeks of Ixekizumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis: The IXORA-PEDS Randomized Clinical Trial.

Importance: About 1% of children and adolescents worldwide are affected by plaque psoriasis. Objective: To evaluate the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis. Design, Setting, and Participants: This multicenter randomized clinical trial (IXORA-PEDS) evaluated pediatric patients with plaque psoriasis. Participants were aged 6 years to younger than 18 years; had moderate to severe psoriasis, which was defined as Psoriasis Area and Severity Index (PASI) of 12 or higher, static Physician's Global Assessment (sPGA) score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline; were candidates for phototherapy or systemic therapy; or had psoriasis that was not adequately controlled by topical therapies. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021. Interventions: Pediatric patients were randomized 2:1 to receive either a weight-based dose of ixekizumab every 4 weeks or placebo. After a 12-week placebo-controlled period, patients entered a 48-week, open-label ixekizumab maintenance period (weeks 12-60), followed by an extension period that lasted through 108 weeks. A substudy evaluated the randomized withdrawal of ixekizumab after week 60. Main Outcomes and Measures: Efficacy outcomes at week 108 included the percentage of patients achieving 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline; an sPGA score of 0 or 1 or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale. Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs, serious AEs, and AEs of special interest, as well as improvement from baseline in a range of challenging body areas. Missing data for categorical outcomes were imputed using modified nonresponder imputation. Results: A total of 171 patients (mean [SD] age, 13.5 [3.04] years; 99 female children [57.9%]) were randomized to either ixekizumab (n = 115) or placebo (n = 56). Of 166 patients who entered the maintenance period, 139 (83.7%) completed week 108 of the trial. Primary and gated secondary end points were sustained through week 108, with patients achieving PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]). Fifty-five patients (78.5%) reported an Itch Numeric Rating Scale improvement of 4 points or higher. In patients who received ixekizumab, at week 108, clearance of nail psoriasis was reported in 68.1% (n = 28), clearance of palmoplantar psoriasis was reported in 90.0% (n = 10), clearance of scalp psoriasis was reported in 76.2% (n = 83), and clearance of genital psoriasis was reported in 87.5% (n = 24). There were no new safety findings during weeks 48 to 108 of the trial, including no new cases of inflammatory bowel disease or candida infection. Conclusions and Relevance: Results of this study showed improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis among pediatric patients who received ixekizumab, and these response rates were sustained through week 108 of the trial. Safety of ixekizumab was consistent with previously reported findings in this population and the known safety profile of this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT03073200.

Number Needed to Treat Network Meta-Analysis to Compare Biologic Drugs for Moderate-to-Severe Psoriasis.

INTRODUCTION: Number needed to treat (NNT) estimates are a practical metric to help identify the most effective therapies. Our objective is to compare 11 biologic drugs for moderate-to-severe psoriasis in terms of NNT. METHODS: The NNT data were obtained from a Bayesian network meta-analysis of 42 double-blind, randomized, phase 3 clinical trials for 11 biologics (adalimumab, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab, and ustekinumab). We determined NNT to achieve Psoriasis Area and Severity Index (PASI) 75/90/100 responses at weeks 4, 8, 12, 16, and 48/52 and Dermatology Life Quality Index (DLQI) response 0, 1 at week 12. RESULTS: Highest efficacy (lowest NNT) was with brodalumab and ixekizumab for PASI 90 at weeks 4, 8, and 12; ixekizumab for PASI 90/100 at week 16; and brodalumab for PASI 100 at week 12. After 48/52 weeks, risankizumab had the highest efficacy for PASI 90/100 overlapping with guselkumab, brodalumab, and ixekizumab for PASI 90 and with brodalumab and ixekizumab for PASI 100. Ixekizumab had the highest efficacy for DLQI (0,1) at week 12. CONCLUSIONS: Brodalumab and ixekizumab had the lowest NNTs for achieving PASI responses at early time points and were not significantly different than risankizumab and guselkumab after 48/52 weeks.

Cumulative Clinical Benefits of Biologics in the Treatment of Patients with Moderate-to-Severe Psoriasis over 1 Year: a Network Meta-Analysis.

INTRODUCTION: Both early clinical improvement and long-term maintenance of clinical efficacy of treatments matter to patients with psoriasis. We compared cumulative clinical benefits of treatment with biologics over 1 year based on the area under the curve (AUC) for Psoriasis Area and Severity Index (PASI) 100 and PASI 90 responses in patients with moderate-to-severe psoriasis using a network meta-analysis (NMA). METHODS: Published phase 3 randomized, placebo- or active-controlled clinical trial data for biologics approved for the treatment of moderate-to-severe psoriasis were obtained from a systematic literature review up to 30 September 2020. Eighteen clinical trials that included data from baseline to 48 or 52 weeks where AUC could be calculated were included. Data were compared using a fixed-effect model with a separate random-effect baseline model to account for effects of the placebo arm. Cumulative clinical benefit was estimated using the AUC for PASI 100 and PASI 90 responses (complete and almost-complete skin clearance, respectively). Normalized AUC was compared using Bayesian NMA. Cumulative days of response were calculated using normalized AUC and study duration. RESULTS: Interleukin (IL)-17 and IL-23 inhibitors demonstrated greater cumulative clinical benefits for both PASI 100 and PASI 90 versus IL-12/23 and tumor necrosis factor inhibitors. Over 52 weeks, cumulative days with PASI 100 were greatest with ixekizumab [158.7 (95% credible interval, 147.4, 170.0) days] followed by risankizumab [154.0 (144.9, 163.4) days]; PASI 90 days were greatest with risankizumab [249.3 (239.5, 259.2) days] followed by ixekizumab [238.8 (227.1, 250.8) days]. Both ixekizumab and risankizumab showed greater cumulative days with PASI 100 or PASI 90 responses versus secukinumab [117.9 (110.7, 125.2) and 215.5 (208.2, 223.1) days, respectively] and greater cumulative days with PASI 100 versus guselkumab [130.7 (120.5, 140.9) days]. CONCLUSION: For complete and almost-complete skin clearance, ixekizumab and risankizumab provided the greatest cumulative clinical benefits over 1 year.

Long-term efficacy and safety of ixekizumab: A 5-year analysis of the UNCOVER-3 randomized controlled trial.

OBJECTIVE: To report the efficacy and safety of the approved ixekizumab (IXE) dose over 5 years from UNCOVER-3 (NCT01646177). METHODS: Patients (N = 1346) were randomized 1:2:2:2 to receive subcutaneous injections of placebo, etanercept 50 mg twice weekly, or IXE 80 mg every 2 weeks or every 4 weeks after an initial dose of IXE 160 mg, respectively. At week 12, patients entered the long-term extension period with dosing of IXE every 4 weeks and could escalate to every 2 weeks after week 60. Efficacy was reported for the IXE every 2 weeks/every 4 weeks group of the intent-to-treat population. Safety was reported for patients who received at least 1 dose of IXE every 2 or every 4 weeks. RESULTS: Using modified nonresponder imputation, 78.8%/67.1%/46.2% of patients receiving the approved dose of IXE every 2 weeks/every 4 weeks (n = 385) achieved ≥75%, ≥90%, or 100% improvement from baseline in the Psoriasis Area and Severity Index, respectively, at week 264; static Physician's Global Assessment score of 0/1 and 0 responses were 69.2% and 45.3%, respectively. Infections were the most observed treatment-emergent adverse event (72.7% of patients). LIMITATIONS: Lack of comparison treatment group after week 12. CONCLUSION: IXE demonstrates sustained efficacy and consistent safety through 264 weeks in patients using the approved dose.

Epidemiology of psoriasis in hard-to-treat body locations: data from the Danish skin cohort.

BACKGROUND: Having psoriasis in hard-to-treat areas, i.e. the scalp, face, palms, soles, nails, and genitals, respectively, can impair patients' quality of life. We investigated the prevalence of hard-to-treat body locations of psoriasis, and described patients' clinical and demographic characteristics, and quality of life impacts in a population-based cohort. METHODS: We performed a cross-sectional study using a total of 4016 adults (≥18 years) with psoriasis from the Danish Skin Cohort. Groups were compared to patients without involvement of hard-to-treat areas. RESULTS: The most frequently affected hard-to-treat area was the scalp (43.0%), followed by the face (29.9%), nails (24.5%), soles (15.6%), genitals (14.1%), and palms (13.7%), respectively. Higher prevalence was generally seen with increasing psoriasis severity. Among all patients 64.8, 42.4, and 21.9% of patients had involvement of ≥1, ≥2, or ≥ 3 hard-to-treat areas. Those with involvement of certain hard-to-treat areas such as hands, feet, and genitals had clinically relevant DLQI impairments. Having involvement of one hard-to-treat area was significantly associated with other hard-to-treat areas affected even after adjusting for age, sex, and psoriasis severity. CONCLUSION: Psoriasis commonly affects hard-to-treat locations, even in patients with mild disease. For some of these areas, patient-reported disease burden, e.g. as measured by DLQI, is impaired.

Rapid Response of Biologic Treatments of Moderate-to-Severe Plaque Psoriasis: A Comprehensive Investigation Using Bayesian and Frequentist Network Meta-analyses.

INTRODUCTION: Rapid improvement of psoriasis is valued by patients and should be considered to be an important factor in treatment selection. We investigated Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) response rates within the first 12 weeks of treatment to compare the rapid response of 11 biologic therapies for moderate-to-severe psoriasis using Bayesian and Frequentist network meta-analyses (NMA). METHODS: A systematic literature review was conducted to identify phase 3, double-blind, randomized, controlled trials for adult patients with moderate-to-severe psoriasis treated with interleukin (IL)-17 (brodalumab, ixekizumab, secukinumab), IL-12/-23 (ustekinumab), IL-23 (guselkumab, risankizumab, tildrakizumab), or tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab). Outcome measures extracted from 32 publications were ≥ 75, ≥ 90, or 100% improvement in PASI score (PASI 75, PASI 90, or PASI 100, respectively) at weeks 2, 4, 8, and 12 and DLQI    (0,1), where score (0,1) indicates no effect on patient's life, at week 12. Bayesian NMA (BNMA) used fixed-treatment effect and random-baseline effect, normal independent models. Frequentist NMA (fNMA) was conducted as sensitivity analyses to test the robustness of the findings. RESULTS: Based on BNMA and fNMA, brodalumab and ixekizumab showed the most rapid treatment effects on PASI 75 at weeks 2, 4, and 8 and on PASI 90 and PASI 100 at weeks 2, 4, 8, and 12; ixekizumab overlapped with risankizumab on PASI 75 at week 12. Brodalumab, ixekizumab, and secukinumab yielded higher DLQI (0,1) gains at week 12 compared to all of the other biologics studied. Additional measures of quality of life were not assessed in this report. CONCLUSIONS: Ixekizumab and brodalumab provide the most rapid response and earliest clinical benefit at week 2 among all of the biologics studied, including other biologic treatments such as secukinumab, ustekinumab, guselkumab, adalimumab, and etanercept. BNMA and fNMA results showed similar relative effect estimates and treatment rankings. FUNDING: Eli Lilly and Company.

Basic Considerations for the Use of Monoclonal Antibodies in Migraine.

BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.