Background: Guselkumab, an interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial.

Transcription

1 ORIGINAL ARTICLES 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 1 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, MD f 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 1 year. From the Oregon Medical Research Center a ; K. Papp Clinical Research and Probity Research Inc, Waterloo b ; Dermatology Center, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Center c ; Janssen Research & Development LLC, Spring House d ; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia e ; 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, Reprint requests: Andrew Blauvelt, MD, MBA, Oregon Medical Research Center, 9495 SW Locust St, Suite G, Portland, OR ablauvelt@oregonmedicalresearch.com. Published online January 2, 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 (

2 406 Blauvelt et al MARCH 2017 Methods: Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo/guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 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 1 year. ( J Am Acad Dermatol 2017;76: ) Key words: adalimumab; efficacy; guselkumab; hand and foot psoriasis; nail psoriasis; psoriasis; safety; scalp psoriasis; VOYAGE 1; VOYAGE 2. Psoriasis is a common, chronic, immune-mediated CAPSULE SUMMARY skin disease that is painful, d disfiguring, and disabling, thereby negatively impacting health-related quality of life (HRQoL) to a significant extent. 1 Psoriasis affecting d body regions such as the scalp, nails, hands, and feet can be particularly challenging to treat. 2-5 Elucidation of the pathogenesis of psoriasis 6-8 d has led to effective biologic treatments targeting tumor necrosis factor-alpha (TNF-a), 9-11 both interleukin (IL)-12 and IL-23, 12,13 and, most recently IL and IL-23 alone Guselkumab (CNTO 1959; Janssen Research & Development LLC, Spring House, PA) is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits the intracellular and downstream signaling of IL-23, which is required for terminal differentiation and survival of T helper (Th)17 cells. 22 To confirm earlier findings, we conducted 2 pivotal, phase III trials: VOYAGE 1 and VOYAGE 2. We report efficacy, safety, and patient-reported outcome findings from VOYAGE 1, which compared guselkumab Phase II data demonstrated superior efficacy of guselkumab compared with adalimumab in moderate to severe psoriasis. The phase III VOYAGE 1 study validates the superiority of guselkumab compared with adalimumab, including in difficultto-treat regional disease, through 1 year of treatment. Our results, which show guselkumab is superior to adalimumab for clearing moderate to severe psoriasis, will help clinicians make informed treatment decisions. with adalimumab, a widely used TNF-a inhibitor, and placebo in patients with psoriasis treated continuously for 1 year. Findings from VOYAGE 2, which included a randomized withdrawal period, are published separately. 23 METHODS Patients Eligible patients (aged $18 years) had moderate to severe plaque psoriasis (ie, Investigator Global Assessment [IGA] score $3, Psoriasis Area and Severity Index [PASI] score $12, body surface area involvement $10%) for at least 6 months and were candidates for systemic therapy or phototherapy. Patients were ineligible if they had a history or current signs of a severe, progressive, or uncontrolled medical condition or had current or history of malignancy, except nonmelanoma skin cancer, within 5 years. Patients with history or symptoms of active tuberculosis were excluded. Patients could not participate if they received guselkumab or adalimumab previously;

3 VOLUME 76, NUMBER 3 Blauvelt et al 407 Abbreviations used: AE: adverse event DLQI: Dermatology Life Quality Index f-pga: Fingernail Physician Global Assessment HRQoL: health-related quality of life IGA: Investigator Global Assessment IL: interleukin ISR: injection site reaction NAPSI: Nail Psoriasis Severity Index PASI: Psoriasis Area and Severity Index 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 PGA: Physician Global Assessment PSSD: Psoriasis Symptoms and Signs Diary Th: T helper TNF-a: tumor necrosis factor-alpha other antietnf-a therapy (within 3 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 1 (NCT ) 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 8 weeks through week 44; placebo at weeks 0, 4, and 12 followed by guselkumab 100 mg at weeks 16 and 20, and every 8 weeks through week 44; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 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 2 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 1 study agent administration and were summarized by actual treatment. The proportion of patients with antibodies to guselkumab was summarized for those receiving at least 1 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

4 408 Blauvelt et al MARCH 2017 Fig 1. 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 3 and Table V). In addition, the proportions achieving 75% or greater improvement in PASI score from baseline (PASI 75) along with IGA 0 and 100% improvement in PASI score from baseline (PASI 100) were significantly higher for guselkumab versus placebo at week 16 (Fig 3 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 3 and Table V). Significantly better responses to guselkumab compared with adalimumab were maintained at week 24 (IGA 0 [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 3 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

5 VOLUME 76, NUMBER 3 Blauvelt et al 409 Table I. Overall psoriasis, regional psoriasis, and health-related quality of life assessments Assessment Description and rating scale IGA Investigator Global Assessment 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). PASI Psoriasis Area and Severity Index The severity of psoriatic lesions is assessed in 4 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. ss-iga Scalp-Specific Investigator Global Assessment Scalp lesions are assessed in terms of clinical signs of redness, thickness, and scaliness and are scored on a 5-point scale: 0 = absence of disease, 1 = very mild disease, 2 = mild disease, 3 = moderate disease, 4 = severe disease. NAPSI Nail Psoriasis Severity Index 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. f-pga Fingernail Physician Global Assessment The overall condition of the fingernails is assessed on a 5-point scale: 0 = clear, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe. hf-pga Physician Global Assessment of Hands and/or Feet The severity of psoriasis plaques on the palms and soles is scored on a 5-point scale: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, and 4 = severe. DLQI Dermatology Life Quality Index 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 A higher score indicates more severe disease. PSSD Psoriasis Symptoms and Signs Diary 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 0 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 0 at weeks 24 and 48 (P \.001) (Table V). Safety outcomes During the placebo-controlled period (weeks 0-16), the proportion of patients with at least 1 AE was comparable across treatment groups, and the most commonly reported events were nasopharyngitis and

6 410 Blauvelt et al MARCH 2017 Table II. Coprimary and major secondary end points tested using a fixed-sequence method Guselkumab vs placebo Guselkumab vs adalimumab Study visit no. Coprimary end points* (1) Proportion of patients who achieve IGA 0/1 and PASI 90 O d Wk 16 Major secondary end points* (2) Proportion of patients who achieve IGA 0 d O Wk 24 (3) Proportion of patients who achieve IGA 0/1 d O Wk 24 (4) Proportion of patients who achieve PASI 90 d O Wk 24 (5) Proportion of patients who achieve IGA 0 d O Wk 48 (6) Proportion of patients who achieve IGA 0/1 d O Wk 48 (7) Proportion of patients who achieve PASI 90 d O Wk 48 (8) Change from baseline in DLQI score O d Wk 16 (9) Proportion of patients who achieve IGA 0/1 yz d O Wk 16 (10) Proportion of patients who achieve PASI 90 yz d O Wk 16 (11) Proportion of patients who achieve PASI 75 yz d O Wk 16 (12) Proportion of patients who achieve ss-iga 0/1 x O d Wk 16 (13) Change from baseline in PSSD symptom score O d Wk 16 (14) Proportion of patients who achieve PSSD symptom score 0 k d O Wk 24 DLQI, Dermatology Life Quality Index; IGA 0, Investigator Global Assessment score of 0 (cleared); IGA 0/1, Investigator Global Assessment score of 0 (cleared) or 1 (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 0 (absence of disease) or 1 (very mild disease). *To control the overall type 1 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 2. Psoriasis. Consolidated Standards of Reporting Trials diagram.

7 VOLUME 76, NUMBER 3 Blauvelt et al 411 Table III. Demographic and disease characteristics at baseline; randomized patients Placebo Guselkumab Adalimumab Total Randomized patients, n Age, y Mean 6 SD Men 119 (68.4) 240 (72.9) 249 (74.6) 608 (72.6) Race White 145 (83.3) 262 (79.6) 277 (82.9) 684 (81.7) Asian 23 (13.2) 51 (15.5) 47 (14.1) 121 (14.5) Black 3 (1.7) 6 (1.8) 8 (2.4) 17 (2.0) BMI, kg/m 2 Mean 6 SD Median (IQR) 27.3 ( ) 28.7 ( ) 28.7 ( ) 28.4 ( ) Duration of psoriasis, y Mean 6 SD Body surface area involvement, % Mean 6 SD IGA score, 0-4 Mild, (0.9) 3 (0.4) Moderate, (75.3) 252 (76.6) 241 (72.2) 624 (74.6) Severe, 4 43 (24.7) 77 (23.4) 90 (26.9) 210 (25.1) PASI score, 0-72 Mean 6 SD Median (IQR) 17.4 ( ) 18.6 ( ) 20.0 ( ) 19.0 ( ) Psoriatic arthritis 30 (17.2) 64 (19.5) 62 (18.6) 156 (18.6) Prior treatments Topical agents 154 (88.5) 299 (90.9) 309 (92.8) 762 (91.1) Phototherapy 86 (49.4) 188 (57.3) 180 (53.9) 454 (54.3) Conventional systemic agents 92 (52.9) 210 (63.8) 215 (64.4) 517 (61.8) Biologic agents 34 (19.5) 71 (21.6) 70 (21.0) 175 (20.9) DLQI score [0-30], n Mean 6 SD PSSD score [0-100], n Symptom score Mean 6 SD Sign score Mean 6 SD 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 1 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 2 patients in the guselkumab group (ie, thigh abscess and cellulitis with postoperative wound infection) and 2 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, 1 basal cell carcinoma each in the guselkumab and adalimumab groups) and 2 malignancies (ie, prostate and breast in the guselkumab

8 412 Blauvelt et al MARCH 2017 Table IV. Regional psoriasis characteristics at baseline; randomized patients Placebo Guselkumab Adalimumab Total Randomized patients, n ss-iga score, (86.2) 291 (88.4) 295 (88.3) 736 (87.9) Very mild, 1 5 (3.3) 14 (4.8) 9 (3.1) 28 (3.8) Mild, 2 31 (20.7) 49 (16.8) 54 (18.3) 134 (18.2) Moderate, 3 89 (59.3) 171 (58.8) 175 (59.3) 435 (59.1) Severe, 4 25 (16.7) 57 (19.6) 57 (19.3) 139 (18.9) f-pga score, (56.9) 198 (60.2) 194 (58.1) 491 (58.7) Minimal, 1 11 (11.1) 24 (12.1) 21 (10.8) 56 (11.4) Mild, 2 33 (33.3) 62 (31.3) 66 (34.0) 161 (32.8) Moderate, 3 42 (42.4) 83 (41.9) 90 (46.4) 215 (43.8) Severe, 4 13 (13.1) 29 (14.6) 17 (8.8) 59 (12.0) NAPSI score, (56.9) 194 (59.0) 191 (57.2) 484 (57.8) Mean 6 SD hf-pga score, (25.3) 100 (30.4) 101 (30.2) 245 (29.3) Almost clear, 1 1 (2.3) 10 (10.0) 6 (5.9) 17 (6.9) Mild, 2 15 (34.1) 34 (34.0) 37 (36.6) 86 (35.1) Moderate, 3 21 (47.7) 42 (42.0) 45 (44.6) 108 (44.1) Severe, 4 7 (15.9) 14 (14.0) 13 (12.9) 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 2 results, 23 confirm that 2 injections of guselkumab 100 mg (weeks 0 and 4) and maintenance therapy every 8 weeks effectively treats moderate to severe psoriasis. Guselkumab was superior to placebo by substantial margins at week 16 using 2 rigorous end points (IGA 0/1 and PASI 90). The onset of action of guselkumab was rapid, with significant response as early as week 2 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,

9 VOLUME 76, NUMBER 3 Blauvelt et al 413 IGA 0 / 1 I G A Proportion of patients (%) A 0 * Week B * Week 100 P A S I 7 5 P A S I 9 0 P A S I Proportion of patients (%) C 0 * * * Week D Week E Week Placebo (n = 174) Placebo (n = 165) Guselkumab Guselkumab (n = 329) Adalimumab (n = 334) * P < for guselkumab vs. placebo P < for guselkumab vs. adalimumab Fig 3. 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 0 (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 1 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.

10 414 Blauvelt et al MARCH 2017 Table V. Physician- and patient-reported outcomes at weeks 16, 24, and 48; randomized patients Wk 16 Wk 24 Wk 48 Placebo Guselkumab Adalimumab Guselkumab Adalimumab Guselkumab Adalimumab Physician-reported outcomes IGA, n IGA 0 2 (1.1) 157 (47.7) 88 (26.3) 173 (52.6) 98 (29.3) 166 (50.5) 86 (25.7) IGA 0/1 12 (6.9) 280 (85.1) 220 (65.9) 277 (84.2) 206 (61.7) 265 (80.5) 185 (55.4) PASI, n PASI (0.6) 123 (37.4) 57 (17.1) 146 (44.4) 83 (24.9) 156 (47.4) 78 (23.4) PASI 90 5 (2.9) 241 (73.3) 166 (49.7) 264 (80.2) 177 (53.0) 251 (76.3) 160 (47.9) PASI (5.7) 300 (91.2) 244 (73.1) 300 (91.2) 241 (72.2) 289 (87.8) 209 (62.6) Baseline ss-iga score $2, n ss-iga 0/1* 21 (14.5) 231 (83.4) 201 (70.3) 234 (84.5) 198 (69.2) 217 (78.3) 173 (60.5) Baseline f-pga score $2, n f-pga 0/1* 14 (15.9) 68 (39.1) 88 (50.9) 98 (56.3) 108 (62.4) 130 (74.7) 107 (61.8) NAPSI, n Mean percent improvement Baseline hf-pga score $2, n hf-pga 0/1* 6 (14.0) 66 (73.3) 53 (55.8) 71 (78.9) 54 (56.8) 68 (75.6) 59 (62.1) Patient-reported outcomes DLQI, n Change in DLQI DLQI score [1 at baseline, n DLQI 0/1 7 (4.2) 180 (56.3) 123 (38.6) 195 (60.9) 126 (39.5) 200 (62.5) 124 (38.9) PSSD score, n Change in symptom score Change in sign score Baseline PSSD symptom score $1, n Symptom score of 0 1 (0.8) 67 (27.0) 45 (16.5) 90 (36.3) 59 (21.6) 104 (41.9) 63 (23.1) Baseline PSSD sign score $1, n Sign score of (20.2) 32 (11.7) 73 (29.4) 40 (14.6) 89 (35.9) 51 (18.6) Values are reported as n (%) or mean 6 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.

11 VOLUME 76, NUMBER 3 Blauvelt et al 415 Fig 4. 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 Wk 0-48 Active comparatorecontrolled period Wk Placebo Guselkumab Adalimumab Guselkumab Adalimumab Placebo /guselkumab Patients treated, n Mean duration of follow-up, wk At least 1 AE 86 (49.4) 170 (51.7) 170 (51.1) 243 (73.9) 248 (74.5) 107 (64.8) Common AEs* Nasopharyngitis 17 (9.8) 30 (9.1) 35 (10.5) 83 (25.2) 74 (22.2) 34 (20.6) Upper respiratory 9 (5.2) 25 (7.6) 16 (4.8) 47 (14.3) 42 (12.6) 17 (10.3) tract infection Injection-site erythema 1 (0.6) 6 (1.8) 15 (4.5) 8 (2.4) 22 (6.6) 3 (1.8) Headache 7 (4.0) 12 (3.6) 13 (3.9) 18 (5.5) 25 (7.5) 1 (0.6) Arthralgia 3 (1.7) 11 (3.3) 9 (2.7) 18 (5.5) 16 (4.8) 2 (1.2) Pruritus 10 (5.7) 5 (1.5) 7 (2.1) 8 (2.4) 12 (3.6) 0 Back pain 2 (1.1) 6 (1.8) 4 (1.2) 12 (3.6) 17 (5.1) 1 (0.6) Discontinued study 2 (1.1) 4 (1.2) 3 (0.9) 9 (2.7) 12 (3.6) 1 (0.6) agent because of AE At least 1 SAE 3 (1.7) 8 (2.4) 6 (1.8) 16 (4.9) 15 (4.5) 5 (3.0) Infections 44 (25.3) 85 (25.8) 85 (25.5) 172 (52.3) 167 (50.2) 76 (46.1) Requiring treatment 13 (7.5) 20 (6.1) 24 (7.2) 54 (16.4) 60 (18.0) 25 (15.2) Serious infections (0.6) 2 (0.6) 3 (0.9) 1 (0.6) Malignancies y (0.6) 0 0 NMSC z 0 1 (0.3) 0 2 (0.6) 1 (0.3) 0 MACE x 0 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 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 3 basal cell carcinomas. x Includes sudden cardiac death, myocardial infarction, and stroke.

12 416 Blauvelt et al MARCH 2017 VOYAGE 1 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 Moreover, IL-23 stimulates production of other Th17 cytokines (eg, IL-22) by other cell types, including innate lymphoid type 3 cells and gd T cells 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 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) 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 1. World Health Organization. Global report on psoriasis. Available from: _eng.pdf. Accessed May 31, 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: Tan EST, Chong W-S, Liang Tey H. Nail psoriasis: a review. Am J Clin Dermatol. 2012;13: 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: Wozel G. Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas. Clin Dermatol. 2008;26: Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009; 361: Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T H l7 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445: Lyakh L, Trinchieri G, Provezza L, et al. Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol Rev. 2008;226: Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicenter, double-blind trial. Lancet. 2005;366: Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152: Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58: Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371: Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371: Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasiseresults of two phase 3 trials. N Engl J Med. 2014;371: Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-tosevere psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomized trials. Lancet. 2015;386: Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373: Kopp T, Riedl E, Bangert C, et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature. 2015; 521: Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mab) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133: Gordon KB, Callis Duffin K, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373: Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mab BI for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136: Papp K, Thaci D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015;173: Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Med. 2015; 21: Reich K, Armstrong AW, Foley P, et al. Efficacy and 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

13 VOLUME 76, NUMBER 3 Blauvelt et al 417 and retreatment: results from the Phase 3, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76: Fredriksson T, Pettersson U. Severe psoriasis e oral therapy with a new retinoid. Dermatologica. 1978;157: Rich P, Scher R. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol. 2003;49: Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)ea simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19: Mathias SD, Feldman SR, Crosby RD, et al. Measurement properties of a patient reported outcome measure assessing psoriasis severity: the Psoriasis Symptoms and Signs Diary. J Dermatol Treat. 2016;27: Feldman SR, Mathias SD, Schenkel B, et al. Development of a patient-reported outcome questionnaire for use in adults with moderate-to-severe plaque psoriasis: the Psoriasis Symptoms and Signs Diary. J Dermatol Surg. 2016;20: Revicki DA, Willian MK, Menter A, et al. Relationship between clinical response to therapy and health-related quality of life outcomes in patients with moderate to severe plaque psoriasis. Dermatology. 2008;216: Viswanathan HN, Chau D, Milmont CE, et al. Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoriasis. J Dermatol Treat. 2015;26: Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A dysfunction phenotypes Inform possible clinical effects from anti-il-17a therapies. J Investig Dermatol. 2015;135: Aggarwal S, Ghilardi N, Xie M-H, et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of Interleukin-17. J Biol Chem. 2003;278: Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17eproducing helper T cells. Nature Immunol. 2007;8: Ness-Schwickerath KJ, Jin C, Morita CT. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells. J Immunol. 2010;184: Villanova F, Flutter B, Tosi I, et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp441 ILC3 in psoriasis. J Investig Dermatol. 2014;134: Ward NL, Umetsu DT. A new player on the psoriasis block: IL-17A- and IL-22-producing innate lymphoid cells. J Investig Dermatol. 2014;134: Teunissen MBM, Marius Munneke J, Bernink JH, et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR1 ILC3 in lesional skin and blood of psoriasis patients. J Investig Dermatol. 2014;134: Blauvelt A. New concepts in the pathogenesis and treatment of psoriasis: key roles for IL-23, IL-17A, and TGF-b1. Expert Rev Dermatol. 2007;2: Humira [package insert]. Chicago, IL: Abbott Laboratories; Enbrel [package insert]. Thousand Oaks, CA: Amgen Inc; Remicade [package insert]. Horsham, PA: Janssen Biotech Inc; Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 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: Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol. 2013;27: 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 2 study through 5 years of follow-up. Br J Dermatol. 2015;172:

14 This e-print is distributed with the support of Janssen