Benefits Over Five Years of Ixekizumab Treatment in Patients With Psoriasis Involving Challenging Body Areas

Challenging body areas include the scalp, face, palmoplantar surfaces (ie, palms and soles), nails, intertriginous areas, and genitalia. Psoriasis involving challenging body areas is associated with a higher degree of disease severity,^1,2 and can be challenging to treat.^3,4 Additionally, psoriasis involving challenging body areas carries a significant burden on patients, disproportionately impacts their quality of life,^5-7 and has worse patient-reported outcomes.⁶ Furthermore, patients with psoriasis involving the face have a higher risk of psoriasis in the scalp, genitalia, and nails; similarly, patients with psoriasis involving the soles have a higher risk of palms and nail involvement.⁸

Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A,⁹ is an approved treatment for moderate-to-severe plaque psoriasis. In the phase III randomized UNCOVER-3 trial (NCT01646177), ixekizumab demonstrated sustained efficacy and consistent safety through 264 weeks in patients with moderate-to-severe plaque psoriasis.¹⁰ Ixekizumab has also been shown to confer cumulative clinical benefits, calculated as area under the curve (AUC) and expressed as total days of benefit realized by patients.¹¹ In the phase IV randomized head-to-head IXORA-R trial (NCT03573323), patients with moderate-to-severe plaque psoriasis treated for 24 weeks with ixekizumab vs the IL-23 inhibitor guselkumab experienced greater cumulative clinical benefits, with more days at 90% and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI90 and PASI100, respectively), more days when psoriasis did not impact the quality of life, and more itch-free days.¹² In a meta-analysis of phase III data of approved treatments of moderate-to-severe psoriasis, ixekizumab showed the greatest cumulative benefits for complete clearance (ie, PASI 100) responses compared to all the other analyzed biologics.^13,14 However, long-term data on clear responses and cumulative clinical benefits are not well documented for patients with psoriasis involving challenging body areas. To address this knowledge gap, clear responses, and cumulative clinical benefits were assessed over 5 years of ixekizumab treatment in patients with moderate-to-severe plaque psoriasis with and without involvement of challenging body areas at baseline.

Study Design and Patient Population This post hoc analysis included patients with moderate-tosevere plaque psoriasis who participated in the UNCOVER-3 trial (NCT01646177) and who were treated with the approved dose of ixekizumab through 264 weeks (ie, 5 years). The study design of this randomized, double-blinded, placebo-controlled, active-controlled, multicenter, phase III trial has been previously described.^10,15 Briefly, patients (N=1,346) were randomly assigned in a 1:2:2:2 ratio to receive subcutaneous injections of placebo, 50 mg etanercept twice weekly, or 160 mg ixekizumab starting dose followed by 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for the induction dosing period (from week 0 to week 12). At week 12, all patients entered a long-term extension period during which they received ixekizumab Q4W through week 264; after week 60, patients could escalate dosing to ixekizumab Q2W at the patient's and investigator's discretion. An institutional review board reviewed and approved study protocols and informed consent forms at each participating site. The study was conducted according to the principles of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. Outcome and Statistical Analysis This post hoc analysis was conducted on the ixekizumab intentto- treat population of the UNCOVER-3 trial, including patients treated with ixekizumab Q2W or Q4W during the induction dosing period and the long-term extension period, excluding data from visits with titrated Q2W long-term dosing. Response rates for complete skin clearance were assessed from week 2 to 264 and presented as the proportions of patients achieving 100% improvement from baseline in their PASI score (PASI100). The PASI is a tool that assesses the extent of body-surface involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of desquamation (scaling), erythema, and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for no psoriasis to 72 for the most severe disease.¹⁶ Data presented are observed. Cumulative clinical benefits of ixekizumab treatment were determined at week 264 as the least-squares mean of the percentage of maximum AUC for PASI100 and PASI% improvement and expressed as cumulative clearance days. Missing data in categorical variables were imputed with non-responder imputation (NRI); missing data in continuous variables were imputed with modified baseline observation carried forward (mBOCF). Statistical differences for cumulative clearance days between patients with and without involvement of each challenging special body area at baseline were calculated via analysis of covariance (ANCOVA), adjusted for baseline PASI and pooled sites.

A total of 385 patients were analyzed from the UNCOVER-3 population treated with ixekizumab: 349 with scalp involvement vs 36 without, 152 with facial involvement (1 patient was not assessed for facial PsO) vs 232 without, 96 with palmoplantar involvement vs 289 without, 229 with nail involvement vs 156 without (Table 1). Specifically, the proportions of patients with challenging body areas at baseline were 90.6% with scalp involvement, 39.6% with facial involvement, 24.9% with palmoplantar involvement, and 59.5% with nail involvement. Baseline Characteristics Demographics and baseline characteristics were rather balanced across the subgroups of patients with baseline involvement of challenging body areas and were consistent with the overall patient population (Table 1). At baseline, the overall patient population had a mean (standard deviation [SD]) age of 45.6 (13.1) years, included mainly males (n=254, 66.0%), was slightly obese with a body mass index of 30.2 kg/m² (7.1), had psoriasis symptoms for 17.8 (12.2) years, had a psoriasis involvement of 28.0% of the body surface area, and some patients had concurrent psoriatic arthritis (n=77, 20.0%). Most patients were biologic-naïve

(n=327, 84.9%), with a few patients (n=58, 15.1%) having previously used biologic therapies. Mean (SD) scores for PASI, static Physician Global Assessment (sPGA), and Dermatology Life Quality Index (DLQI) were 20.7 (8.2), 3.5 (0.6), and 12.4 (6.9), respectively. Response Rates Proportions of patients achieving PASI100 were numerically similar between patients with and without scalp and nail involvement at baseline (Figure 1). Conversely, more patients without vs with facial involvement achieved PASI100 at week 108 (65.1% vs 47.1%), at week 156 (69.2% vs 56.5%), and at week 204 (69.4% vs 62.7%), and more patients without vs with palmoplantar involvement achieved PASI100 at week 60 (68.8% vs 47.6%), at week 108 (63.8% vs 39.7%), at week 156 (71.1% vs 43.1%), at week 204 (71.3% vs 52.1%), and at week 264 (70.6% vs 51.2%). Cumulative Clinical Benefits At week 264 (ie, 1848 days), cumulative clinical benefits for PASI100 and PASI% improvement were high in both patient groups, with no statistically significant differences (P>0.05) in most instances between patients with and without baseline involvement of challenging body areas (Figure 2). Specifically, the cumulative days of clinical benefits for PASI100 in patients with vs without baseline involvement of challenging body areas were, respectively: scalp involvement 821.8 days vs 724.6 days (difference 12%, P=0.442), facial involvement 844.8 days vs 793.2 days (difference 6%, P=0.515), palmoplantar involvement 693.5 days vs 853.6 days (difference -23%, P=0.098), and nail involvement 845.0 days vs 765.5 days (difference 9%, P=0.382).

Similarly, the cumulative days of clinical benefits for PASI% improvement in patients with vs without baseline involvement of challenging body areas were, respectively: scalp involvement 1,639.0 days vs 1,526.6 days (difference 7%, P=0.079), facial involvement 1,641.7 days vs 1,618.1 days (difference 1%, P=0.553), palmoplantar involvement 1,601.7 days vs 1,637.3 days (difference -2%, P=0.463), and nail involvement 1,679.8 days vs 1,554.1 days (difference 7%, significant P=0.006).

Psoriasis involving challenging body areas is associated with higher degrees of disease severity and often influences treatment decisions.^1,2 According to recent guidelines derived from the International Psoriasis Council, patients with psoriasis involving challenging body areas are categorized as candidates for systemic therapy even when the total involved body surface area is less than 10%.¹ Additionally, psoriasis involving challenging body areas can

be challenging to treat^3,4 and carries a higher burden and impact on patients' quality of life.^5-7 When evaluating treatment efficacy, assessing the cumulative clinical benefits is an intuitive and instructive method that captures the magnitude and speed of onset, as well as the maintenance of clinical response over time.¹⁴ Here, we found out that, in most cases, clearance responses and cumulative clinical benefits over 5 years of ixekizumab treatment were similar in patients with and without involvement of challenging body areas at baseline. Clear responses and cumulative clinical benefits were high in patients with and without individual challenging body areas, as well as among different challenging body areas. These findings imply that, regardless of baseline involvement of challenging body areas, patients treated with ixekizumab can achieve similar clear responses and cumulative clinical benefits over long periods of time. In the analyzed population, baseline involvement of challenging body areas was 1.7 to 2.6 times higher than observed in a large prospective United States cohort, including 3,825 patients with psoriasis, where Merola et al identified the following prevalence for psoriasis phenotypes: scalp 52%, palmoplantar 14%, and nail 23%.¹⁷ One limitation of this analysis is that data were evaluated post hoc. We also focused only on patients with involvement of the scalp, face, palms, soles, and nails, excluding other challenging body areas (eg, intertriginous areas and genitalia), which were not specifically evaluated in the UNCOVER-3 trial. Another limitation included the small sample size of patients without scalp involvement at baseline (N=36); thus, these results should be interpreted with caution. In conclusion, in most instances, patients with moderate-tosevere plaque psoriasis treated with ixekizumab over 5 years achieved similar clearance responses and cumulative clinical benefits regardless of baseline involvement of the analyzed challenging body areas: scalp, face, palms, soles, and nails.

AB Gottlieb has received honoraria as an advisory board member; and serves as a consultant for Amgen, AnaptysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Dice Therapeutics, Eli Lilly and Company, Janssen, Highlights Therapeutic, Novartis, Sanofi, UCB, and Xbiotech; and has received research/educational grants from AnaptysBio, Bristol-Myers Squibb, Immunotherapeutics AG, Janssen, MoonLake. Novartis, and UCB Pharma (all paid to Mount Sinai School of Medicine). A. Armstrong has served as a consultant, speaker, and/or investigator for AbbVie, Almirall, Arcutis, ASLAN Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, EPI Health, Incyte Corporation, Janssen, LEO Pharma, Modernizing Medicine, Nimbus Therapeutics, Novartis, Ortho Dermatologics, PAREXEL, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB Pharma. A. Blauvelt has served as a speaker (received honoraria) for AbbVie, Eli Lilly and Company, Pfizer, and UCB, served as a scientific adviser (received honoraria) for AbbVie, Abcentra, Aclaris, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Apogee, Arcutis, Arena, Aslan, Athenex, Bluefin Biomedicine, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, CTI BioPharma, Dermavant, EcoR1, Eli Lilly and Company, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, InnoventBio, Janssen, Landos, Leo, Lipidio, Microbion, Merck, Monte Rosa Therapeutics, Nektar, Novartis, Overtone Therapeutics, Paragon, Pfizer, Q32 Bio, Rani, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, Sun Pharma, Takeda, TLL Pharmaceutical, TrialSpark, UCB Pharma, Union, Ventyx, Vibliome, and Xencor, and has acted as a clinical study investigator (institution has received clinical study funds) for AbbVie, Acelyrin, Allakos, Almirall, Alumis, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol- Myers Squibb, Concert, Dermavant, Eli Lilly and Company, Evelo, Evommune, Galderma, Incyte, Janssen, Leo, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, UCB Pharma, and Ventyx. C. E. M. Griffiths has received honoraria and/or research funds from: AbbVie, Almirall, Anaptysbio, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Eli Lilly and Company, Evelo Biosciences, Inmagene, Kyowa Kirin, Janssen, Novartis, ONO Pharmaceuticals, Pfizer, Sun Pharma, and UCB Pharma. A. Pinter has served as an investigator and/or speaker and/or advisor for AbbVie, Almirall Hermal, Amgen, Biogen, BioNTech, BMS, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galderma, GlaxoSmithKline, Hexal, Janssen, LEO Pharma, MC2 Therapeutics, Medac, Merck Serono, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pascoe Natural Healthcare, Pfizer, Regeneron, Roche, Sandoz, Sanofi, Schering- Plough, Tigercat Pharma, UCB Pharma, and Zuellig Pharma. M. Gooderham has been an investigator, speaker, and/or advisor for AbbVie, Akros Pharma, Amgen, Arcutis, Aristea Therapeutics, Bausch Health, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Incyte Corporation, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, MoonLake, Nimbus Therapeutics, Novartis, Pfizer, Regeneron, Reistone Biopharma, Roche, Sanofi, Sun Pharma, and UCB Pharma. M. Lomaga has been an advisory board member and/or investigator for AbbVie, Amgen, Dermavant, Dermira, Devonian Health Group, Eli Lilly and Company, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sun Pharma, UCB Pharma, and Valeant Pharmaceuticals. R. T. Burge is a shareholder of Eli Lilly and Company and is an employee of Eli Lilly and Company and the University of Cincinnati, Cincinnati, OH, USA. BW Konicek and K. See are employees and shareholders of Eli Lilly and Company. M. Feely McDonald is associate staff at Mount Sinai Hospital, Mount Sinai West, and Mount Sinai Morningside; is a current employee and shareholder of Eli Lilly and Company; has received consulting,

travel, or speaker fees from American Academy of Dermatology, Aerolase, Castle Biosciences, CeraVe-L'Oreal, DREAM USA, Galderma Aesthetics, Glow Recipe, La Roche-Posay - L'Oreal, Revian, Sonoma Pharmaceuticals, Sun Pharma, and Suneva Medical. M. McKean-Matthews is an employee of Syneos Health. T. Mabuchi has received lecture fees from Maruho Co., Ltd., Janssen Pharmaceutical K.K., Celgene Corporation, Kyowa Kirin Co., Ltd., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., and UCB Japan Co., Ltd. and has received manuscript fees from Kyowa Kirin Co., Ltd., Torii Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K. and has received clinical research funding from Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., AbbVie GK., Bristol-Myers Squibb Company, and Parexel and has received research/educational grants from Maruho Co., Ltd., Kyowa Kirin Co., Ltd., Torii Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., LEO Pharma K.K., and Sun Pharma Japan Ltd. Funding sources: This study was funded by Eli Lilly and Company, which contributed to study design, data collection, data analysis, data interpretation, manuscript preparation, and publication decisions. Data availability statement: Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available for request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date for data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank, or annotated case report forms, will be provided in a secure datasharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. Clinical trial number: NCT01646177

Eli Lilly and Company would like to thank the clinical trial participants and their caregivers, without whom this work would not be possible. The authors would like to acknowledge Elsa Inman PhD and Marcus Ngantcha MS employees of Eli Lilly and Company, for medical and statistical review, respectively. Medical writing assistance was provided by Elisa Di Carlo PhD, an employee of Eli Lilly and Company.

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Alice B. Gottlieb alicegottliebderm@gmail.com