Efficacy and safety of guselkumab, an anti interleukin 23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis Results from the phas[.]
ORIGINAL ARTICLE Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparatorecontrolled VOYAGE trial Andrew Blauvelt, MD, MBA,a Kim A Papp, MD, PhD,b Christopher E M Griffiths, MD,c Bruce Randazzo, MD, PhD,d,e Yasmine Wasfi, MD, PhD,d Yaung-Kaung Shen, PhD,d Shu Li, PhD,d and Alexa B Kimball, MPH, MDf Portland, Oregon; Waterloo, Ontario, Canada; Manchester, United Kingdom; Spring House and Philadelphia, Pennsylvania; and Boston, Massachusetts Background: Guselkumab, an interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial Objectives: We sought to compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for year From the Oregon Medical Research Centera; K Papp Clinical Research and Probity Research Inc, Waterloob; Dermatology Center, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Centerc; Janssen Research & Development LLC, Spring Housed; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphiae; and Department of Dermatology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston.f Supported by Janssen Research & Development LLC, Spring House, PA Disclosure: Dr Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, GSK, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi-Genzyme, Sun, UCB, and Valeant, and as a paid speaker for Eli Lilly Dr Papp has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for AbbVie, Akesis, Akros, Allergan, Alza, Amgen, Anacor, Artax, Astellas, AstraZeneca, Baxalta, Baxter, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, CanFite, Celgene, Celtic, Cipher, Dermira, Dow Pharmaceuticals, Eli Lilly, Ferring Pharmaceuticals, Formycon, Forward Pharma, Funxional Therapeutics, Fujisawa, Galderma, Genentech, Genexion, Genzyme, Gilead, GSK, Janssen, Kyowa Hakko Kirin, Leo, Lypanosys, Medimmune, Meiji Seika Pharma, Merck (MSD), Merck-Serono, Mitsubishi Pharma, Mylan, Novartis, NovImmune, Pan Genetics, Pfizer, Regeneron, Roche, Sanofi-Aventis, Stiefel, Takeda, UCB, Vertex, and Valeant Dr Griffiths has received honoraria and/or grants as an investigator, speaker, and/or advisory board member for AbbVie, Eli Lilly, Janssen, Leo, Novartis, Pfizer, Sandoz, and Sun Pharma Dr Kimball has received honoraria as a consultant for AbbVie, BMS, Dermira, Eli Lilly ICOS LLC, Merck, and Novartis; and received grants and/or funding for research or the residency/fellowship program as a principal investigator for AbbVie, Amgen, Boehringer Ingelheim, Dermira, Janssen, Merck, and Novartis Drs Randazzo, Wasfi, Shen, and Li are all employees of Janssen Research & Development LLC (subsidiary of Johnson & Johnson) and own stock in Johnson & Johnson Some of the data reported in this article were presented at the 25th European Academy of Dermatology and Venereology Congress (Vienna, Austria; September 28-October 2, 2016), the 35th Anniversary Fall Clinical Dermatology Conference (Las Vegas, NV; October 20-23, 2016), and Skin Disease Education Foundation 17th Annual Las Vegas Dermatology Seminar (Las Vegas, NV; November 10-12, 2016) Accepted for publication November 19, 2016 Reprint requests: Andrew Blauvelt, MD, MBA, Oregon Medical Research Center, 9495 SW Locust St, Suite G, Portland, OR 97223 E-mail: ablauvelt@oregonmedicalresearch.com Published online December 29, 2016 0190-9622 Ó 2016 by the American Academy of Dermatology, Inc Published by Elsevier, Inc This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/) http://dx.doi.org/10.1016/j.jaad.2016.11.041 J AM ACAD DERMATOL Blauvelt et al n 2016 Methods: Patients were randomized to guselkumab 100 mg (weeks and 4, then every weeks; n = 329); placebo/guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every weeks through week 47; n = 334) Physician-reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient-reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48 Results: Guselkumab was superior (P \ 001) to placebo at week 16 (85.1% vs 6.9% [Investigator Global Assessment score of 0/1 (cleared/minimal)] and 73.3% vs 2.9% [90% or greater improvement in PASI score from baseline (PASI 90)]) Guselkumab was also superior (P \.001) to adalimumab for Investigator Global Assessment 0/1 and PASI 90 at week 16 (85.1% vs 65.9% and 73.3% vs 49.7%), week 24 (84.2% vs 61.7% and 80.2% vs 53.0%), and week 48 (80.5% vs 55.4% and 76.3% vs 47.9%) Furthermore, guselkumab significantly improved patient-reported outcomes through week 48 Adverse event rates were comparable between treatments Limitations: Analyses were limited to 48 weeks Conclusions: Guselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through year ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2016.11.041.) Key words: adalimumab; efficacy; guselkumab; hand and foot psoriasis; nail psoriasis; psoriasis; safety; scalp psoriasis; VOYAGE 1; VOYAGE Psoriasis is a common, with adalimumab, a widely CAPSULE SUMMARY chronic, immune-mediated used TNF-a inhibitor, and skin disease that is painful, placebo in patients with psoPhase II data demonstrated superior disfiguring, and disabling, riasis treated continuously efficacy of guselkumab compared with thereby negatively impacting for year Findings from adalimumab in moderate to severe health-related quality of life VOYAGE 2, which included psoriasis (HRQoL) to a significant a randomized withdrawal extent.1 Psoriasis affecting period, are published The phase III VOYAGE study validates 23 body regions such as the scalp, separately the superiority of guselkumab compared nails, hands, and feet can be with adalimumab, including in difficultparticularly challenging to METHODS to-treat regional disease, through year treat.2-5 Elucidation of the Patients of treatment pathogenesis of psoriasis6-8 Eligible patients (aged Our results, which show guselkumab is has led to effective biologic $18 years) had moderate to superior to adalimumab for clearing treatments targeting tumor nesevere plaque psoriasis moderate to severe psoriasis, will help crosis factor-alpha (TNF-a),9-11 (ie, Investigator Global clinicians make informed treatment both interleukin (IL)-12 and Assessment [IGA] score $3, decisions IL-23,12,13 and, most recently Psoriasis Area and Severity IL-1714-16 and IL-23 alone.17-21 Index [PASI] score $12, Guselkumab (CNTO body surface area involve1959; Janssen Research & Development LLC, Spring ment $10%) for at least months and were House, PA) is a fully human IgG1 lambda monocandidates for systemic therapy or phototherapy clonal antibody that binds to the p19 subunit of IL-23 Patients were ineligible if they had a history or and inhibits the intracellular and downstream current signs of a severe, progressive, or unconsignaling of IL-23, which is required for terminal trolled medical condition or had current or history of differentiation and survival of T helper (Th)17 cells.22 malignancy, except nonmelanoma skin cancer, To confirm earlier findings, we conducted pivotal, within years Patients with history or symptoms phase III trials: VOYAGE and VOYAGE We report of active tuberculosis were excluded Patients could efficacy, safety, and patient-reported outcome findnot participate if they received guselkumab or ings from VOYAGE 1, which compared guselkumab adalimumab previously; other antieTNF-a therapy d d d J AM ACAD DERMATOL Blauvelt et al VOLUME jj, NUMBER j Abbreviations used: AE: DLQI: f-PGA: HRQoL: IGA: IL: ISR: NAPSI: PASI: PASI 75: adverse event Dermatology Life Quality Index Fingernail Physician Global Assessment health-related quality of life Investigator Global Assessment interleukin injection site reaction Nail Psoriasis Severity Index Psoriasis Area and Severity Index 75% or greater improvement in Psoriasis Area and Severity Index score from baseline PASI 90: 90% or greater improvement in Psoriasis Area and Severity Index score from baseline PASI 100: 100% improvement in Psoriasis Area and Severity Index score from baseline PGA: Physician Global Assessment PSSD: Psoriasis Symptoms and Signs Diary Th: T helper TNF-a: tumor necrosis factor-alpha (within months); other treatment targeting IL-12/ 23, IL-17, or IL-23 (6 months); or any systemic immunosuppressants (eg, methotrexate) or phototherapy (4 weeks) Study design VOYAGE (NCT02207231) was a phase III, randomized, double-blind, placebo- and active comparatorecontrolled trial conducted at 101 global sites (December 2014-April 2016) The study comprised an active-comparator period when guselkumab was compared with adalimumab (week 0-48) and a placebo-controlled period (weeks 0-16), after which patients taking placebo crossed over to receive guselkumab through week 48 (Fig 1) Patients were randomized using a permuted block method at baseline in a 2:1:2 ratio to guselkumab 100 mg at weeks 0, 4, 12, and every weeks through week 44; placebo at weeks 0, 4, and 12 followed by guselkumab 100 mg at weeks 16 and 20, and every weeks through week 44; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every weeks through week 47 Central randomization was implemented using an interactive World Wide Web response system (Perceptive Informatics, East Windsor, NJ) To maintain the blind, matching placebos were used An institutional review board or ethics committee approved the study protocol at participating sites; patients provided written informed consent before study initiation Assessments Efficacy was evaluated using the IGA, PASI,24 scalpspecific IGA, fingernail Physician Global Assessment (f-PGA), Nail Psoriasis Severity Index (NAPSI),25 and Physician Global Assessment (PGA) of the hands and/ or feet (Table I) Patient-reported outcomes were assessed using the Dermatology Life Quality Index (DLQI)26 and Psoriasis Symptoms and Signs Diary (PSSD)27,28 (Table I) Safety monitoring included collection of adverse events (AEs) and laboratory testing Antibodies to guselkumab were detected using a highly sensitive and drug-tolerant electrochemiluminescence immunoassay (sensitivity: 3.1 ng/ mL in guselkumab-free serum and 15 ng/mL with serum guselkumab concentrations #3.125 g/mL, exceeding mean trough serum guselkumab levels) Statistical analyses Coprimary end points were the proportions of patients achieving an IGA score of cleared/minimal disease (IGA 0/1) and 90% or greater improvement in PASI score from baseline (PASI 90) at week 16 in the guselkumab group compared with placebo The primary and major secondary analyses were tested in a fixed sequence to control for multiplicity (Table II) All randomized patients were included in the primary and selected secondary efficacy analyses; data were analyzed by randomized treatment group The coprimary end points and binary major secondary end points were analyzed using a Cochran-Mantel-Haenszel x statistical test stratified by investigator site With a sample size of approximately 750 patients, the power to detect a significant difference was more than 99% for both coprimary end points Continuous response parameters were compared using an analysis of variance model with investigator site as a covariate All statistical testing was performed 2-sided (a = 0.05) Patients who discontinued study agent because of lack of efficacy or an AE of psoriasis worsening or who started a protocol-prohibited psoriasis treatment were considered nonresponders (binary end points) or had baseline values carried over (continuous end points) Other patients with missing data were considered nonresponders for binary end points (nonresponder imputation) and had last observation carried forward for continuous end points (and all PSSD end points) Safety analyses included all patients receiving at least study agent administration and were summarized by actual treatment The proportion of patients with antibodies to guselkumab was summarized for those receiving at least dose of the biologic RESULTS At baseline, 837 patients were randomized to placebo (n = 174), guselkumab (n = 329), or adalimumab (n = 334) Overall, 6.9% (12 of 174), 8.5% (28 of 329), and 15.6% (52 of 334) of patients J AM ACAD DERMATOL Blauvelt et al n 2016 Fig Psoriasis Study schema discontinued treatment in the placebo, guselkumab, and adalimumab groups, respectively, through week 48 (Fig 2) Demographic and disease characteristics were comparable across treatment groups at baseline (Tables III and IV) Clinical responses Guselkumab was superior to placebo and/or adalimumab for the coprimary end points and all major secondary end points (all P \ 001) Compared with placebo, significantly higher proportions of patients taking guselkumab achieved IGA 0/1 (6.9% vs 85.1%) and PASI 90 (2.9% vs 73.3%) at week 16 (Fig and Table V) In addition, the proportions achieving 75% or greater improvement in PASI score from baseline (PASI 75) along with IGA and 100% improvement in PASI score from baseline (PASI 100) were significantly higher for guselkumab versus placebo at week 16 (Fig and Table V) Guselkumab was superior to adalimumab as measured by the proportion of patients achieving IGA 0/1 (85.1% vs 65.9%), PASI 90 (73.3% vs 49.7%), and PASI 75 (91.2% vs 73.1%) at week 16 (Fig and Table V) Significantly better responses to guselkumab compared with adalimumab were maintained at week 24 (IGA [52.6% vs 29.3%], IGA 0/1 [84.2% vs 61.7%], and PASI 90 [80.2% vs 53.0%]) and at week 48 (50.5% vs 25.7%, 80.5% vs 55.4%, and 76.3% vs 47.9%, respectively) (Fig and Table V) Likewise, PASI 100 responses in the guselkumab group were significantly better than those in the adalimumab group at weeks 24 and 48 (P \.001) In addition, higher proportions of patients taking guselkumab attained response in higher PASI categories compared with adalimumab at week 48 (Fig 4) After initiating guselkumab at week 16, patients in the placebo cross-over group achieved responses similar to those observed in the guselkumab group (Fig 3) Regional psoriasis measures Regional psoriasis was evaluated based on assessments using scalp-specific IGA; f-PGA; NAPSI; and PGA of the hands and/or feet as described in Table I The proportion of patients in the guselkumab group achieving scalp-specific IGA 0/1 (absent/very mild scalp psoriasis) was significantly higher compared with placebo (83.4% vs 14.5%, P \ 001) at week 16; significantly better responses to guselkumab versus adalimumab were observed at weeks 24 and 48 (both P \.001) (Table V) The proportion of patients achieving f-PGA 0/1 (cleared/minimal) and percent improvement in NAPSI score were significantly higher for guselkumab versus placebo at week 16 (P \.001) (Table V) Although the f-PGA responses were comparable at week 24, guselkumab was superior to adalimumab by week 48 (P = 038, Table V) Mean percent improvements in NAPSI score were comparable between guselkumab and adalimumab at weeks 24 and 48 (Table V) The proportion of patients achieving PGA 0/1 of the hands and/or feet (clear/almost clear) was significantly higher for guselkumab versus placebo at week 16, and responses to guselkumab were superior to J AM ACAD DERMATOL Blauvelt et al VOLUME jj, NUMBER j Table I Overall psoriasis, regional psoriasis, and health-related quality of life assessments Assessment IGA Investigator Global Assessment PASI Psoriasis Area and Severity Index ss-IGA Scalp-Specific Investigator Global Assessment NAPSI Nail Psoriasis Severity Index f-PGA Fingernail Physician Global Assessment hf-PGA Physician Global Assessment of Hands and/or Feet DLQI Dermatology Life Quality Index PSSD Psoriasis Symptoms and Signs Diary Description and rating scale At a given time point, psoriatic lesions are graded by the investigator for induration, erythema, and scaling on a scale of 0-4: cleared (0), minimal (1), mild (2), moderate (3), or severe (4) The severity of psoriatic lesions is assessed in body regions: the head, trunk, and upper and lower extremities, which account for 10%, 30%, 20%, and 40% of the total BSA, respectively Each of these areas is assessed separately for erythema, induration, and scaling, which are each rated on a scale of 0-4 Total score ranges from 0-72; a higher score indicates more severe disease Scalp lesions are assessed in terms of clinical signs of redness, thickness, and scaliness and are scored on a 5-point scale: = absence of disease, = very mild disease, = mild disease, = moderate disease, = severe disease A target nail (ie, the nail most affected by psoriasis) is divided into quadrants, which are examined for the presence of nail matrix psoriasis (ie, pitting, leukonychia, red spots in the lunula, nail plate crumbling) and nail bed psoriasis (ie, onycholysis, oil drop dyschromia, splinter hemorrhages, subungual hyperkeratosis) on a scale of 0-4; total score ranges from 0-8; higher scores indicate more severe disease The overall condition of the fingernails is assessed on a 5-point scale: = clear, = minimal, = mild, = moderate, and = severe The severity of psoriasis plaques on the palms and soles is scored on a 5-point scale: = clear, = almost clear, = mild, = moderate, and = severe Ten questions related to the effect of skin problems on aspects of life (ie, symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment) during the previous week are answered by the patient, for an overall score of 0-30 A higher score indicates more severe disease Symptoms (ie, itch, pain, stinging, burning, and skin tightness) and signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) of psoriasis are graded (0-10 scale) by the patient in a daily diary A higher score indicates more severe symptoms and signs of psoriasis BSA, Body surface area adalimumab at week 24 (P \ 001) and week 48 (P \.045) (Table V) HRQoL measures At week 16, improvement from baseline in DLQI score was significantly greater for guselkumab compared with placebo (mean change 11.2 vs 0.6), as were the proportions of patients achieving DLQI score 0/1 (no impact of psoriasis on HRQoL) (both P \.001) (Table V) At weeks 24 and 48, both improvements from baseline in DLQI score and proportions of patients achieving DLQI 0/1 were significantly higher for guselkumab versus adalimumab (P \.001) (Table V) At week 16, the improvement from baseline in PSSD symptom score was significantly greater for guselkumab versus placebo (mean change 41.9 vs 3.0); mean changes in PSSD sign score were similarly favorable for guselkumab (both P \ 001) (Table V) Likewise, at weeks 24 and 48, mean changes in PSSD scores for guselkumab were significantly greater than those for adalimumab (P \ 001) (Table V) The proportions of patients achieving a PSSD symptom score of with guselkumab and adalimumab, respectively, were 36.3% and 21.6% at week 24, and the significantly better response to guselkumab was maintained at week 48 (P \.001) Similar results were observed for the proportions of patients achieving a PSSD sign score of at weeks 24 and 48 (P \.001) (Table V) Safety outcomes During the placebo-controlled period (weeks 016), the proportion of patients with at least AE was comparable across treatment groups, and the most commonly reported events were nasopharyngitis and J AM ACAD DERMATOL Blauvelt et al n 2016 Table II Coprimary and major secondary end points tested using a fixed-sequence method Coprimary end points* (1) Proportion of patients who achieve IGA 0/1 and PASI 90 Major secondary end points* (2) Proportion of patients who achieve IGA (3) Proportion of patients who achieve IGA 0/1 (4) Proportion of patients who achieve PASI 90 (5) Proportion of patients who achieve IGA (6) Proportion of patients who achieve IGA 0/1 (7) Proportion of patients who achieve PASI 90 (8) Change from baseline in DLQI score (9) Proportion of patients who achieve IGA 0/1yz (10) Proportion of patients who achieve PASI 90yz (11) Proportion of patients who achieve PASI 75yz (12) Proportion of patients who achieve ss-IGA 0/1x (13) Change from baseline in PSSD symptom score (14) Proportion of patients who achieve PSSD symptom score 0k Guselkumab vs placebo Guselkumab vs adalimumab O d Wk 16 d d d d d d O d d d O O d O O O O O O d O O O d d O Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Study visit no 24 24 24 48 48 48 16 16 16 16 16 16 24 DLQI, Dermatology Life Quality Index; IGA 0, Investigator Global Assessment score of (cleared); IGA 0/1, Investigator Global Assessment score of (cleared) or (minimal); PASI 75, 75% or greater improvement from baseline in Psoriasis Area and Severity Index score; PASI 90, 90% or greater improvement from baseline in Psoriasis Area and Severity Index score; PSSD, Psoriasis Symptoms and Signs Diary; ss-IGA 0/1, scalp-specific Investigator Global Assessment score of (absence of disease) or (very mild disease) *To control the overall type error rate, the primary analysis and major secondary analyses were tested using a fixed sequence method Specifically, the first major secondary end point was tested only if the coprimary end points were positive, and subsequent end points were tested only if the preceding end point was positive y Tested for noninferiority of the guselkumab group compared with the adalimumab group z Tested for superiority of the guselkumab group compared with the adalimumab group x Included only randomized patients with scalp psoriasis who had an ss-IGA score $2 at baseline and who achieved $2-grade improvement k Included only randomized patients with PSSD symptom score $1 at baseline Fig Psoriasis Consolidated Standards of Reporting Trials diagram J AM ACAD DERMATOL Blauvelt et al VOLUME jj, NUMBER j Table III Demographic and disease characteristics at baseline; randomized patients Randomized patients, n Age, y Mean SD Men Race White Asian Black BMI, kg/m2 Mean SD Median (IQR) Duration of psoriasis, y Mean SD Body surface area involvement, % Mean SD IGA score, 0-4 Mild, Moderate, Severe, PASI score, 0-72 Mean SD Median (IQR) Psoriatic arthritis Prior treatments Topical agents Phototherapy Conventional systemic agents Biologic agents DLQI score [0-30], n Mean SD PSSD score [0-100], n Symptom score Mean SD Sign score Mean SD Placebo Guselkumab Adalimumab Total 174 329 334 837 44.9 12.90 119 (68.4) 43.9 12.74 240 (72.9) 42.9 12.58 249 (74.6) 43.7 12.72 608 (72.6) 145 (83.3) 23 (13.2) (1.7) 262 (79.6) 51 (15.5) (1.8) 277 (82.9) 47 (14.1) (2.4) 684 (81.7) 121 (14.5) 17 (2.0) 28.9 6.89 27.3 (24.1-33.1) 29.7 6.22 28.7 (25.5-32.9) 29.8 6.48 28.7 (25.2-33.5) 29.6 6.47 28.4 (25.2-33.2) 17.6 12.44 17.9 12.27 17.0 11.27 17.5 11.91 25.8 15.93 28.3 17.10 28.6 16.66 27.9 16.70 131 (75.3) 43 (24.7) 252 (76.6) 77 (23.4) (0.9) 241 (72.2) 90 (26.9) (0.4) 624 (74.6) 210 (25.1) 20.4 8.74 17.4 (14.4-23.1) 30 (17.2) 22.1 9.49 18.6 (15.6-25.5) 64 (19.5) 22.4 8.97 20.0 (16.0-26.1) 62 (18.6) 21.9 9.15 19.0 (15.4-25.4) 156 (18.6) 154 86 92 34 (88.5) (49.4) (52.9) (19.5) 170 13.3 7.12 129 299 188 210 71 (90.9) (57.3) (63.8) (21.6) 322 14.0 7.48 249 309 180 215 70 (92.8) (53.9) (64.4) (21.0) 328 14.4 7.29 274 762 454 517 175 48.3 23.77 54.4 24.63 53.9 25.79 53.0 25.03 53.6 20.34 56.9 21.30 58.5 21.73 56.9 21.34 (91.1) (54.3) (61.8) (20.9) 820 14.0 7.33 652 Values are reported as n (%), unless otherwise indicated BMI, Body mass index; DLQI, Dermatology Life Quality Index; IGA, Investigator Global Assessment; IQR, interquartile range; PASI, Psoriasis Area and Severity Index; PSSD, Psoriasis Symptoms and Signs Diary upper respiratory tract infection (Table VI) Serious AEs and AEs leading to study agent discontinuation occurred infrequently and in similar proportions of patients for each treatment (Table VI) Rates of overall infections and infections requiring antibiotic treatment were comparable across treatment groups (Table VI) Two patients in the adalimumab group experienced serious infections (both cellulitis) One nonmelanoma skin cancer (ie, basal cell carcinoma) was reported in the guselkumab group, and no other malignancies occurred in any group One myocardial infarction (ie, major adverse cardiovascular event) occurred in each of the guselkumab and adalimumab groups through week 16 The types and patterns of AEs reported through week 48 were similar to those reported during the placebo-controlled period (Table VI) The proportions of patients with at least AE, an AE leading to discontinuation, or a serious AE were similar in the guselkumab and adalimumab groups (Table VI) Between weeks 16 and 48, serious infections were reported in patients in the guselkumab group (ie, thigh abscess and cellulitis with postoperative wound infection) and patients in the adalimumab group (ie, abdominal abscess and staphylococcal pneumonia with a fatal outcome) Overall infections and infections requiring antibiotic treatment occurred at comparable rates across treatment groups (Table VI) Two additional nonmelanoma skin cancers (ie, basal cell carcinoma each in the guselkumab and adalimumab groups) and malignancies (ie, prostate and breast in the guselkumab J AM ACAD DERMATOL Blauvelt et al n 2016 Table IV Regional psoriasis characteristics at baseline; randomized patients Randomized patients, n ss-IGA score, 0-4 Very mild, Mild, Moderate, Severe, f-PGA score, 0-4 Minimal, Mild, Moderate, Severe, NAPSI score, 0-8 Mean SD hf-PGA score, 0-4 Almost clear, Mild, Moderate, Severe, Placebo Guselkumab Adalimumab Total 174 150 (86.2) (3.3) 31 (20.7) 89 (59.3) 25 (16.7) 99 (56.9) 11 (11.1) 33 (33.3) 42 (42.4) 13 (13.1) 99 (56.9) 4.7 1.94 44 (25.3) (2.3) 15 (34.1) 21 (47.7) (15.9) 329 291 (88.4) 14 (4.8) 49 (16.8) 171 (58.8) 57 (19.6) 198 (60.2) 24 (12.1) 62 (31.3) 83 (41.9) 29 (14.6) 194 (59.0) 4.9 2.03 100 (30.4) 10 (10.0) 34 (34.0) 42 (42.0) 14 (14.0) 334 295 (88.3) (3.1) 54 (18.3) 175 (59.3) 57 (19.3) 194 (58.1) 21 (10.8) 66 (34.0) 90 (46.4) 17 (8.8) 191 (57.2) 4.6 2.03 101 (30.2) (5.9) 37 (36.6) 45 (44.6) 13 (12.9) 837 736 (87.9) 28 (3.8) 134 (18.2) 435 (59.1) 139 (18.9) 491 (58.7) 56 (11.4) 161 (32.8) 215 (43.8) 59 (12.0) 484 (57.8) 4.7 2.01 245 (29.3) 17 (6.9) 86 (35.1) 108 (44.1) 34 (13.9) Values are reported as n (%), unless otherwise indicated f-PGA, Fingernail Physician Global Assessment; hf-PGA, Physician Global Assessment of hands and/or feet; NAPSI, Nail Psoriasis Severity Index; ss-IGA, scalp-specific Investigator Global Assessment group) were reported through week 48 No additional major adverse cardiovascular event occurred after week 16 A single suicide attempt was reported in a patient taking adalimumab Incidence rates of candidiasis and neutropenia were low and comparable between groups, and no events of Crohn’s disease were reported through week 48 Through week 48, the proportion of patients with an injection site reaction (ISR) (2.2% vs 9.0%) and the proportion of injections associated with ISRs (0.5% vs 1.2%) were lower for guselkumab compared with adalimumab; most ISRs were mild Rates of abnormal laboratory results were low, and no between-group differences were noted Antibodies to guselkumab were detected in 26 of 492 patients (5.3%) through week 44; titers were generally low (81% #1:320) No association was observed between antibody development and reduced efficacy or ISR occurrence DISCUSSION Our findings, together with the VOYAGE results,23 confirm that injections of guselkumab 100 mg (weeks and 4) and maintenance therapy every weeks effectively treats moderate to severe psoriasis Guselkumab was superior to placebo by substantial margins at week 16 using rigorous end points (IGA 0/1 and PASI 90) The onset of action of guselkumab was rapid, with significant response as early as week compared with placebo Guselkumab was also superior to adalimumab, which is a widely used and effective subcutaneous TNF-a inhibitor, at the week-16 end points of IGA 0/1, PASI 90, and PASI 75 Response rates continued to improve with guselkumab beyond week 16 At weeks 24 and 48, approximately half of all patients in the guselkumab group achieved complete clearance (IGA 0), which is associated with optimal HRQoL for patients with psoriasis.29,30 Patient-reported outcome end points (PSSD and DLQI) based on total change, or indicating minimal/no impact on HRQoL or no symptoms or signs of psoriasis, demonstrated guselkumab responses superior to placebo at week 16 and adalimumab at weeks 24 and 48 This study assessed multiple body areas where psoriasis is challenging to treat, and guselkumab was highly effective in all regions Guselkumab was superior to placebo at week 16 and to adalimumab at weeks 24 and 48, indicating complete or nearly complete clearance of scalp and hand/foot psoriasis in at least 75% of guselkumab-treated patients Based on both the proportion of patients with clear/ minimal fingernail psoriasis (f-PGA 0/1) and the mean percent improvement in NAPSI score, guselkumab was superior to placebo at week 16 Nail responses were comparable between active treatments at weeks 24 and 48, and guselkumab was superior to adalimumab for f-PGA 0/1 at week 48 Rates and types of AEs, serious AEs, and abnormal laboratory results were generally comparable between the guselkumab and placebo groups through week 16, and between the guselkumab and adalimumab groups through week 48 Rates of serious infections, J AM ACAD DERMATOL Blauvelt et al VOLUME jj, NUMBER j IGA / IGA Proportion of patients (%) 100 80 † 60 † 40 † † 20 * * 12 16 20 24 28 32 36 40 44 48 A 12 16 20 24 28 32 36 40 44 48 B Week PASI 75 Week PASI 90 PASI 100 Proportion of patients (%) 100 80 † † 60 † † 40 † 20 * * * 12 16 20 24 28 32 36 40 44 48 12 16 20 24 28 32 36 40 44 48 C † Week Placebo (n = 174) D Placebo (n = 165) Week Guselkumab 12 16 20 24 28 32 36 40 44 48 E Guselkumab (n = 329) Week Adalimumab (n = 334) * P < 0.001 for guselkumab vs placebo † P < 0.001 for guselkumab vs adalimumab Fig Psoriasis Clinical efficacy through week 48 Proportion of patients achieving (A) IGA 0/1, (B) IGA 0, (C) PASI 75, (D) PASI 90, and (E) PASI 100 responses IGA 0/1, Investigator Global Assessment score of cleared (0) or minimal (1); IGA 0, Investigator Global Assessment score of (cleared); PASI 75, 75% or greater improvement in Psoriasis Area and Severity Index score from baseline; PASI 90, 90% or greater improvement in Psoriasis Area and Severity Index score from baseline; PASI 100, 100% improvement in Psoriasis Area and Severity Index score from baseline malignancies, and major adverse cardiovascular events were low and comparable across treatment groups No notable differences in the incidence of neutropenia or candidiasis were observed between the guselkumab and control groups No AEs of Crohn’s disease occurred in any treatment group, and suicide attempt was reported in the adalimumab group The number of injections and proportions of patients with ISRs were higher for adalimumab compared with guselkumab The size and duration of this study may not allow for assessment of uncommon events or those with a long latency; however, longer-term guselkumab treatment is being evaluated in ongoing study extensions Wk 16 Physician-reported outcomes IGA, n IGA IGA 0/1 PASI, n PASI 100 PASI 90 PASI 75 Baseline ss-IGA score $2, n ss-IGA 0/1* Baseline f-PGA score $2, n f-PGA 0/1* NAPSI, n Mean percent improvement Baseline hf-PGA score $2, n hf-PGA 0/1* Patient-reported outcomes DLQI, n Change in DLQI DLQI score [1 at baseline, n DLQI 0/1 PSSD score, n Change in symptom score Change in sign score Baseline PSSD symptom score $1, n Symptom score of Baseline PSSD sign score $1, n Sign score of Wk 24 Wk 48 Placebo Guselkumab Adalimumab Guselkumab Adalimumab Guselkumab Adalimumab 174 (1.1) 12 (6.9) 174 (0.6) (2.9) 10 (5.7) 145 21 (14.5) 88 14 (15.9) 99 0.9 57.89 43 (14.0) 329 157 (47.7) 280 (85.1) 329 123 (37.4) 241 (73.3) 300 (91.2) 277 231 (83.4) 174 68 (39.1) 194 34.4 42.46 90 66 (73.3) 334 88 (26.3) 220 (65.9) 334 57 (17.1) 166 (49.7) 244 (73.1) 286 201 (70.3) 173 88 (50.9) 191 38.0 53.87 95 53 (55.8) 329 173 (52.6) 277 (84.2) 329 146 (44.4) 264 (80.2) 300 (91.2) 277 234 (84.5) 174 98 (56.3) 194 49.8 44.16 90 71 (78.9) 334 98 (29.3) 206 (61.7) 334 83 (24.9) 177 (53.0) 241 (72.2) 286 198 (69.2) 173 108 (62.4) 191 49.4 60.04 95 54 (56.8) 329 166 (50.5) 265 (80.5) 329 156 (47.4) 251 (76.3) 289 (87.8) 277 217 (78.3) 174 130 (74.7) 194 68.1 43.00 90 68 (75.6) 334 86 (25.7) 185 (55.4) 334 78 (23.4) 160 (47.9) 209 (62.6) 286 173 (60.5) 173 107 (61.8) 191 61.4 49.20 95 59 (62.1) 170 0.6 6.36 168 (4.2) 129 3.0 19.56 4.1 17.87 129 (0.8) 129 322 11.2 7.24 320 180 (56.3) 249 41.9 24.61 44.6 22.00 248 67 (27.0) 248 50 (20.2) 328 9.3 7.80 319 123 (38.6) 274 35.4 28.45 39.7 26.44 273 45 (16.5) 274 32 (11.7) 322 11.6 7.55 320 195 (60.9) 249 44.0 24.57 47.2 22.19 248 90 (36.3) 248 73 (29.4) 328 9.5 7.89 319 126 (39.5) 274 36.0 28.36 40.1 26.49 273 59 (21.6) 274 40 (14.6) 322 11.8 7.87 320 200 (62.5) 249 45.3 25.51 47.9 23.08 248 104 (41.9) 248 89 (35.9) 328 9.2 8.27 319 124 (38.9) 274 32.5 31.14 36.6 29.28 273 63 (23.1) 274 51 (18.6) n 2016 J AM ACAD DERMATOL Values are reported as n (%) or mean SD DLQI, Dermatology Life Quality Index score; f-PGA, fingernail Physician Global Assessment; hf-PGA, Physician Global Assessment of hands and/or feet; IGA, Investigator Global Assessment; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; PASI 75, 75% or greater improvement from baseline in Psoriasis Area and Severity Index; PASI 90, 90% or greater improvement from baseline in Psoriasis Area and Severity Index; PASI 100, 100% or greater improvement from baseline in Psoriasis Area and Severity Index; PSSD, Psoriasis Symptoms and Signs Diary; ss-IGA, scalpspecific Investigator Global Assessment *Includes only patients also achieving $2-grade improvement in ss-IGA and hf-PGA scores and $1-grade improvement in f-PGA score 10 Blauvelt et al Table V Physician- and patient-reported outcomes at weeks 16, 24, and 48; randomized patients J AM ACAD DERMATOL Blauvelt et al 11 VOLUME jj, NUMBER j Fig Psoriasis Distribution of PASI responses at week 48 PASI, Psoriasis Area and Severity Index; PASI 50, 50% or greater improvement in Psoriasis Area and Severity Index score from baseline; PASI 75, 75% or greater improvement in Psoriasis Area and Severity Index score from baseline; PASI 90, 90% or greater improvement in Psoriasis Area and Severity Index score from baseline; PASI 100, 100% improvement in Psoriasis Area and Severity Index score from baseline Table VI Cumulative rates of key safety events; treated patients Wk 0-16 Placebo-controlled period Patients treated, n Mean duration of follow-up, wk At least AE Common AEs* Nasopharyngitis Upper respiratory tract infection Injection-site erythema Headache Arthralgia Pruritus Back pain Discontinued study agent because of AE At least SAE Infections Requiring treatment Serious infections Malignanciesy NMSCz MACEx Wk 0-48 Active comparatorecontrolled period Wk 16-48 Placebo Guselkumab Adalimumab Guselkumab Adalimumab Placebo /guselkumab 174 15.88 329 16.27 333 16.14 329 46.47 333 45.56 165 31.88 86 (49.4) 170 (51.7) 170 (51.1) 243 (73.9) 248 (74.5) 107 (64.8) 17 (9.8) (5.2) 30 (9.1) 25 (7.6) 35 (10.5) 16 (4.8) 83 (25.2) 47 (14.3) 74 (22.2) 42 (12.6) 34 (20.6) 17 (10.3) 10 2 12 11 15 13 (4.5) (3.9) (2.7) (2.1) (1.2) (0.9) 18 18 12 (2.4) (5.5) (5.5) (2.4) (3.6) (2.7) 22 25 16 12 17 12 (1.8) (25.5) (7.2) (0.6) 0 (0.3) 16 172 54 2 (4.9) (52.3) (16.4) (0.6) (0.6) (0.6) (0.3) 15 167 60 (0.6) (4.0) (1.7) (5.7) (1.1) (1.1) (1.7) 44 (25.3) 13 (7.5) 0 0 (1.8) (3.6) (3.3) (1.5) (1.8) (1.2) (2.4) 85 (25.8) 20 (6.1) 0 (0.3) (0.3) 85 24 (6.6) (7.5) (4.8) (3.6) (5.1) (3.6) (4.5) (50.2) (18.0) (0.9) (0.3) (0.3) (1.8) (0.6) (1.2) (0.6) (0.6) 76 25 (3.0) (46.1) (15.2) (0.6) 0 Values are reported as n (%) AE, Adverse event; MACE, major adverse cardiovascular events; NMSC, nonmelanoma skin cancers; SAE, serious adverse event *Occurred in at least 5% of patients in any treatment group through wk 48 y Includes malignancies other than NMSC (ie, prostate and breast cancer) z Includes basal cell carcinomas x Includes sudden cardiac death, myocardial infarction, and stroke 12 Blauvelt et al VOYAGE confirms the role of IL-23 in the pathogenesis of psoriasis When compared with TNF-a blockade, selective targeting of the IL-23 pathway provides more psoriasis-specific cytokine inhibition with a higher degree of efficacy while maintaining a favorable safety profile.31 IL-23 is a key driver of Th17 cell differentiation and survival and an upstream regulator of IL-17A, a central proinflammatory effector cytokine implicated in psoriasis pathogenesis.32-34 Moreover, IL-23 stimulates production of other Th17 cytokines (eg, IL-22) by other cell types, including innate lymphoid type cells and gd T cells.35-37 Therefore, inhibition of IL-23 blocks downstream production of IL-17A and IL-22 by Th17 cells and other cell types Because many IL-17Aproducing cells are dependent on IL-23 for survival, inhibition of IL-23 may reduce the number of these pathogenic cells.38 This may explain the long duration of effect and allow for the convenient dosing interval of guselkumab compared with both antieTNF-a and anti-IL-17 agents.39-43 Our findings, together with those from VOYAGE 2,23 demonstrate the superior efficacy of guselkumab compared with adalimumab in psoriasis, including regional disease of the scalp, nails, and hands/feet, and a positive safety profile Although the wellcharacterized long-term safety findings reported for a related treatment that blocks both IL-12 and IL-23 (ustekinumab)44-46 provides relevant information for selective blockade of IL-23 with guselkumab, ongoing study extensions will be important for defining the efficacy and safety of guselkumab beyond the 1-year period reported here The authors thank Cynthia Arnold, Janssen Scientific Affairs LLC, Spring House, PA, and Cynthia Guzzo, MD, HireGenics, Duluth, GA, for their editorial assistance and writing support and Philippe Szapary, MD, MSCE, and Michael Song, MD, Janssen Research & Development LLC, Spring House, PA, for their critical review of this manuscript REFERENCES World Health Organization Global report on psoriasis Available from: http://apps.who.int/iris/bitstream/10665/204417/1/ 9789241565189_eng.pdf Accessed May 31, 2016 Kragballe K, Menter A, Lebwohl M, et al Long-term management of scalp psoriasis: perspectives from the international psoriasis council J Dermatol Treat 2013;24:188-192 Tan EST, Chong W-S, Liang Tey H Nail psoriasis: a review Am J Clin Dermatol 2012;13:375-388 Chung J, Callis Duffin K, Takeshita J, et al Palmoplantar psoriasis is associated with greater impairment of healthrelated quality of life compared with moderate to severe plaque psoriasis J Am Acad Dermatol 2014;71:623-632 Wozel G Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas Clin Dermatol 2008;26:448-459 J AM ACAD DERMATOL n 2016 Nestle FO, Kaplan DH, Barker J Psoriasis N Engl J Med 2009; 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2002 Enbrel [package insert] Thousand Oaks, CA: Amgen Inc; 1998 Remicade [package insert] Horsham, PA: Janssen Biotech Inc; 1998 Cosentyx [package insert] East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015 Taltz [package insert] Indianapolis, IN: Eli Lilly and Company; 2016 Papp K, Gottlieb AB, Naldi L, et al Safety surveillance for ustekinumab and other psoriasis treatments from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) J Drugs Dermatol 2015;14:706-714 Kimball AB, Papp KA, Wasfi Y, et al Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to years in the PHOENIX study J Eur Acad Dermatol Venereol 2013;27:1535-1545 Langley RG, Lebwohl M, Krueger GG, et al Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX study through years of follow-up Br J Dermatol 2015;172:1371-1383 ... safety of guselkumab, an anti- IL -23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate- to- severe psoriasis with randomized withdrawal J AM ACAD DERMATOL Blauvelt... Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate- to- severe psoriasis: results from the PHOENIX study through years of follow-up Br J Dermatol... guselkumab compared with both antieTNF-a and anti- IL-17 agents.39-43 Our findings, together with those from VOYAGE 2 ,23 demonstrate the superior efficacy of guselkumab compared with adalimumab