An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Guselkumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa: A phase 2 randomized study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that causes substantial physical, emotional and psychological burdens. Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin-23, has demonstrated high levels of efficacy in the treatment of inflammatory diseases, including psoriasis and psoriatic arthritis. OBJECTIVE: To evaluate the effect of guselkumab on the treatment of HS, a phase 2, multicentre, randomized, placebo-controlled, double-blind, proof-of-concept study was conducted. METHODS: Patients ≥18 years of age with moderate-to-severe HS for ≥1 year were randomized to (1) guselkumab 200 mg by subcutaneous (SC) injection every 4 weeks (q4w) through Week 36 (guselkumab SC); (2) guselkumab 1200 mg intravenously (IV) q4w for 12 weeks, then switched to guselkumab 200 mg SC q4w from Weeks 12 through 36 (guselkumab IV); or (3) placebo for 12 weeks, with re-randomization to guselkumab 200 mg SC q4w at Weeks 16 through 36 (placebo → guselkumab 200 mg) or guselkumab 100 mg SC at Weeks 16, 20, 28 and 36 and placebo at Weeks 24 and 32 (placebo → guselkumab 100 mg). End points included HS clinical response (HiSCR) and patient-reported outcomes. RESULTS: Although guselkumab SC or guselkumab IV resulted in numerically higher HiSCR versus placebo at Week 16 (50.8%, 45.0%, 38.7%, respectively), statistical significance was not achieved. Numerically greater improvements in patient-reported outcomes were also observed for guselkumab SC and guselkumab IV versus placebo at Week 16. Through Week 40, no clear differences to suggest a dose response were observed for HiSCR and patient-reported outcomes. CONCLUSIONS: Despite modest improvements, the primary end point was not met and the overall findings do not support the efficacy of guselkumab in the treatment of HS. CLINICALTRIALS: gov: NCT03628924.

Continuous treatment with guselkumab maintains clinical responses through 4 years in patients with moderate-to-severe psoriasis: results from VOYAGE 1.

OBJECTIVES: To evaluate the efficacy of guselkumab through four years of continuous treatment for psoriasis. METHODS: In the phase 3 VOYAGE 1 trial, 837 patients with moderate-to-severe psoriasis were randomized to receive guselkumab 100 mg every-8-weeks, placebo, or adalimumab 40 mg every-2-weeks. Patients in the placebo and adalimumab groups crossed over to receive guselkumab at weeks 16/52, respectively; eligible patients received open-label guselkumab through week 204. Efficacy endpoints (i.e., PASI 75/90/100, IGA 0/1, and IGA 0) were analyzed in the guselkumab group using different methodologies: prespecified treatment failure rules (TFR, patients discontinued due to lack of efficacy, psoriasis worsening, or protocol-prohibited psoriasis treatment considered nonresponders); nonresponder imputation (NRI, patients with missing data counted as nonresponders); and As Observed (OBS, no imputation). Safety was evaluated through week 204. RESULTS: At week 204, PASI 90 response rates were 82.2%, 68.4%, and 84.3%, respectively, based on TFR, NRI, and OBS analyses; corresponding proportions at week 52 were 79.7%, 75.5%, and 80.6%. Similarly, PASI 75, PASI 100, IGA 0/1, and IGA 0 responses were maintained from week 52 through week 204. No new safety signals were identified. CONCLUSIONS: High efficacy response rates were maintained through four years of continuous guselkumab treatment for psoriasis.

Consistent safety profile with up to 5 years of continuous treatment with guselkumab: Pooled analyses from the phase 3 VOYAGE 1 and VOYAGE 2 trials of patients with moderate-to-severe psoriasis.

BACKGROUND: Guselkumab effectively treats moderate-to-severe psoriasis. OBJECTIVE: To evaluate the cumulative safety experience of guselkumab using pooled data from the VOYAGE 1 and 2 studies through 5 years. METHODS: Patients were randomized to guselkumab, placebo with crossover to guselkumab at week 16, or adalimumab. The studies were identical through week 24. VOYAGE 1 evaluated continuous guselkumab treatment (adalimumab-crossover-to-guselkumab at week 52), while VOYAGE 2 assessed randomized withdrawal/retreatment (weeks 28-76). Open-label guselkumab treatment was administered starting at week 52 in VOYAGE 1 and week 76 in VOYAGE 2 and continued through week 252. Pooled safety data were adjusted by exposure and analyzed in the guselkumab groups, including placebo-crossover-to-guselkumab (n = 1221) and adalimumab-crossover-to-guselkumab (n = 500), through week 264. RESULTS: Patients were followed for a total of 7166 patient-years (PY). Overall, 1349 of 1721 guselkumab-treated patients (78.4%) continued treatment through week 252. The rates of adverse and serious adverse events were 149/100 PY and 5.01/100 PY, respectively. Rates of adverse events of interest were low: serious infections (0.85/100 PY), nonmelanoma skin cancer (0.34/100 PY), malignancies other than nonmelanoma skin cancer (0.45/100 PY), and major adverse cardiovascular events (0.29/100 PY). Year-to-year variability was evident, but no increasing trend was observed. LIMITATIONS: No direct treatment comparisons were possible after week 52. CONCLUSION: The safety profile remained consistent and favorable during 5 years of continuous guselkumab treatment of psoriasis.

Serious Gastrointestinal-Related Adverse Events Among Psoriasis Patients Treated With Guselkumab in VOYAGE 1 and VOYAGE 2.

BACKGROUND: Anti-interleukin (IL)-17 biologic agents used to treat psoriasis are associated with onset/exacerbation of inflammatory bowel disease (IBD). OBJECTIVES: To determine the incidence of IBD or serious gastrointestinal-related adverse events (GI SAEs) in patients with moderate-to-severe psoriasis treated with guselkumab, an IL-23p19 inhibitor that indirectly inhibits IL-17, through 4 years in the phase 3 VOYAGE 1 and VOYAGE 2 trials. METHODS: Patients were randomized to guselkumab 100 mg every-8-weeks or placebo→guselkumab (week 16), or adalimumab. In VOYAGE 1, all patients received open-label guselkumab starting at week 52. In VOYAGE 2, eligible patients were treated with guselkumab or placebo based on clinical response starting at week 28 and received open-label guselkumab starting at week 76. Cumulative incidence rates of IBD and other GI SAEs were calculated as events per 100 patient-years (PY) through week 204. IBD was defined as AEs of Crohn’s disease or ulcerative colitis. Data were summarized for all guselkumab-treated patients for years 1-4. RESULTS: Of 1721 guselkumab-treated patients, 1612 were exposed for ≥1 year, 1545 for ≥2 years, 1454 for ≥3 years, and 661 for ≥4 years. For all patients through week 204, the cumulative rate of GI SAEs was 0.45/100PY. Event rates remained stable with longer duration of exposure, ranging from 0.36 to 0.57/100PY. No new or exacerbated cases of IBD were reported. CONCLUSIONS: No cases of IBD were observed and rates of GI SAEs were low through 4 years of treatment with guselkumab in two large trials of patients with psoriasis. J Drugs Dermatol. 2021;20(8):855-860. doi:10.36849/JDD.6216 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Consistent response to guselkumab treatment between Hispanic and non-Hispanic patients with psoriasis: an analysis from VOYAGE 1 and VOYAGE 2.

INTRODUCTION: In VOYAGE 1 (NCT02207231) and VOYAGE 2 (NCT02207244), guselkumab, an interleukin-23 blocker, was safe and effective in patients with moderate-to-severe plaque psoriasis. METHODS: Patients who self-identified as Hispanic (n = 117) or non-Hispanic (n = 1686) were randomized to guselkumab, placebo, or adalimumab. Efficacy assessments included Psoriasis Area and Severity Index (PASI), Investigator's Global Assessment (IGA), and Dermatology Life Quality Index (DLQI). RESULTS: At week 16, treatment differences for guselkumab versus placebo in the Hispanic and non-Hispanic populations were 67.4 (95% confidence interval 50.4, 84.4) and 77.2 (73.5, 80.8) percentage points for IGA 0/1 and 59.2 (41.9, 76.4) and 69.2 (65.7, 72.7) percentage points for PASI 90, respectively. Treatment differences for guselkumab versus adalimumab were 25.9 (6.5, 45.3) and 17.5 (12.8, 22.3) percentage points for IGA 0/1 and 21.4 (-0.1, 42.9) and 23.5 (18.2, 28.9) percentage points for PASI 90, respectively. Week 24 results were similar. Adverse event frequency was greater in adalimumab- versus guselkumab-treated patients in the Hispanic population only through weeks 16 and 28. In both populations, DLQI 0/1 responses were greater in guselkumab-treated versus placebo- and adalimumab-treated patients at week 16 and versus adalimumab-treated patients at week 24. CONCLUSIONS: Guselkumab safety and efficacy were consistent between Hispanic and non-Hispanic populations.

Maintenance of clinical response and consistent safety profile with up to 3 years of continuous treatment with guselkumab: Results from the VOYAGE 1 and VOYAGE 2 trials.

BACKGROUND: Long-term maintenance treatment is required for patients with psoriasis. OBJECTIVES: To evaluate the efficacy and safety of guselkumab in patients with moderate to severe psoriasis through 3 years of treatment. METHODS: In 2 ongoing, phase 3 trials of guselkumab (VOYAGE 1 and VOYAGE 2), the proportions of patients achieving at least 90% and 100% improvement in the Psoriasis Area and Severity Index (PASI 90 and PASI 100, respectively) and Investigator's Global Assessment (IGA) scores of 0/1 and 0 were summarized for the guselkumab group (including placebo-to-guselkumab crossover). Patients who met treatment failure rules were considered nonresponders. Safety outcomes (rates/100 patient-years [PY]) were evaluated based on data pooled across studies through week 156. RESULTS: Three-year response rates for the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 82.8% and 77.2% for PASI 90, 50.8% and 48.8% for PASI 100, 82.1% and 83.0% for IGA score of 0/1, and 53.1% and 52.9% for IGA score of 0. Safety event rates across studies occurred through week 156 as follows: serious adverse events, 5.68/100 PY; serious infections, 1.15/100 PY; nonmelanoma skin cancers, 0.28/100 PY; malignancies other than nonmelanoma skin cancer, 0.47/100 PY; and major adverse cardiovascular events, 0.28/100 PY. Week 156 and week 100 rates were consistent. LIMITATIONS: There was no comparator arm beyond 1 year. CONCLUSIONS: Guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3 years.

Guselkumab Efficacy after Withdrawal Is Associated with Suppression of Serum IL-23-Regulated IL-17 and IL-22 in Psoriasis: VOYAGE 2 Study.

BACKGROUND: Guselkumab selectively inhibits IL-23 and in psoriasis, produces high clinical responses, including durable maintenance after treatment withdrawal in some patients. The relationships between IL-23 blockade, serum markers downstream of IL-23 signaling, and withdrawal were explored with guselkumab in VOYAGE 2. METHODS: At week 28, patients with ≥90% Psoriasis Area and Severity Index improvement from baseline (PASI 90) were rerandomized to withdrawal and received placebo (n = 182), or maintenance therapy (n = 193). The guselkumab withdrawal group reinitiated guselkumab upon loss of ≥50% of week- 28 PASI improvement or by week 72. Cytokine changes associated with psoriasis recurrence (serum IL-17A, IL-17F, IL-22, and IL-23) after withdrawal were evaluated. RESULTS: Efficacy in the guselkumab maintenance group was sustained through week 72, whereas efficacy diminished in the guselkumab withdrawal group (PASI 90, 86.0% vs. 11.5%). After 20 weeks of retreatment, 80.4% of guselkumab withdrawal patients achieved PASI 90 responses versus baseline. Maintenance of response after withdrawal was associated with suppression of IL-17A, IL-17F, and IL-22. Increases in cytokine levels had poor predictive power for psoriasis reoccurrence as these increases lagged behind increases in PASI scores. CONCLUSION: Upon guselkumab withdrawal, most patients lost clinical response and regained responses with retreatment. Correlation of IL-23 signaling serum cytokines increased with disease recurrence, supporting the role of IL-23 in expansion and maintenance of CD4+ T helper type 17, T helper type 22, and related CD8+ T-cell subsets producing IL-17A, IL-17F, and IL-22.

Improvement in Patient-Reported Outcomes (Dermatology Life Quality Index and the Psoriasis Symptoms and Signs Diary) with Guselkumab in Moderate-to-Severe Plaque Psoriasis: Results from the Phase III VOYAGE 1 and VOYAGE 2 Studies.

BACKGROUND: Health-related quality of life (HRQoL) may be markedly impaired in patients with moderate-to-severe psoriasis. OBJECTIVES: Our objectives were to compare improvements in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) scores between patients receiving guselkumab compared with placebo or adalimumab and to correlate these improvements with skin clearance. METHODS: Pooled phase III VOYAGE 1 and VOYAGE 2 data were evaluated through week 24. At baseline, patients were randomized to guselkumab 100 mg, placebo, or adalimumab 40 mg. At week 16, patients receiving placebo switched to guselkumab. Assessment measures included DLQI percent change from baseline, DLQI 0/1, DLQI minimal clinically important difference (MCID), individual domain scores, PSSD symptoms and signs score = 0, DLQI association with PSSD, Investigator's Global Assessment (IGA), and Psoriasis Area and Severity Index (PASI). RESULTS: Significantly greater improvements from baseline DLQI were observed with guselkumab versus placebo (weeks 8 and 16) and versus adalimumab (week 24; p < 0.001). The proportion of patients achieving DLQI 0/1 ("no impact") at week 24 was higher with guselkumab than with adalimumab (58.9 vs. 40.2%; p < 0.001), and more patients attained a ≥ 4-point reduction in DLQI (MCID) at this timepoint (p < 0.001). Changes in individual DLQI domains were significantly greater for patients receiving guselkumab than for those receiving adalimumab, and among patients with individual baseline domain scores = 3 or 6 (severest impact), more guselkumab recipients than those receiving adalimumab achieved a score = 0 across all domains at week 24. DLQI 0/1 scores were associated with a PSSD symptom or sign score = 0 (no impact) and greater improvement of PASI and IGA (week 24). CONCLUSIONS: Pooled VOYAGE 1/VOYAGE 2 data demonstrated that guselkumab was superior to adalimumab in improving HRQoL, which was associated with greater skin clearance. CLINICAL TRIAL REGISTRATION: NCT02207231 and NCT02207244.

Long-Term Efficacy of Guselkumab for the Treatment of Moderate-to-Severe Psoriasis: Results from the Phase 3 VOYAGE 1 Trial Through Two Years.

BACKGROUND: Due to the chronic nature of psoriasis, it is important to assess the sustained response of treatments over time. OBJECTIVE: To assess the efficacy of continuous treatment with guselkumab (an interleukin-23 blocker) through two years in the phase 3 VOYAGE 1 trial. METHODS: Patients were randomized to placebo, guselkumab, or adalimumab at baseline. Placebo-randomized patients crossed over to guselkumab at week 16 (placebo→guselkumab) and adalimumab-randomized patients crossed over to guselkumab at week 52 (adalimumab→guselkumab); all patients received open-label guselkumab beyond week 52. Efficacy was assessed based on the Psoriasis Area and Severity Index (PASI; proportion of patients achieving ≥75%, 90%, or 100% improvement [PASI 75/90/100]) and the Investigator's Global Assessment (IGA; proportion achieving nearly clear [IGA 0/1] or completely clear [IGA 0]). As pre-specified, efficacy data were analyzed using non-responder imputation (NRI; patients with missing data counted as non-responders) after applying treatment failure rules (TFR; patients meeting TFR counted as non-responders thereafter) through week 48 and by applying TFR only from week 52 through 100. All endpoints were also analyzed using NRI and As Observed methodology for the guselkumab group through week 100. RESULTS: The clinical responses were maintained through week 100 based on all three analyses. Based on pre-specified analyses, proportions of patients who achieved PASI 75, PASI 90, PASI 100, IGA 0/1, and IGA 0 were 94.8%, 82.1%, 49.0%, 82.4%, and 53.8%, respectively, at week 100. Results were similar for the placebo→guselkumab and adalimumab→guselkumab groups at week 100. As expected, proportions of patients achieving these endpoints were similar based on As Observed analyses and slightly lower when the more conservative NRI rules were applied. CONCLUSIONS: High levels of efficacy were maintained through two years of continuous treatment among guselkumab-treated patients, and efficacy improved through two years among adalimumab-treated patients who crossed over to guselkumab at one year. J Drugs Dermatol. 2018;17(8):826-832.

Efficacy of Guselkumab Compared With Adalimumab and Placebo for Psoriasis in Specific Body Regions: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: Psoriasis of the scalp, palms and/or soles, and nails is challenging to treat. Objective: To evaluate the effect of guselkumab on psoriasis in specific body regions. Design, Setting, and Participants: VOYAGE 1 and VOYAGE 2 were, double-blind, placebo- and adalimumab-controlled studies of guselkumab conducted at 101 and 115 global sites, respectively, from November 3, 2014, to May 19, 2016. Patients had moderate to severe plaque psoriasis (Psoriasis Area and Severity Index score ≥12, Investigator's Global Assessment [IGA] score ≥3, and ≥10% body surface area with psoriasis). This post hoc data analysis was performed from February 10 through November 15, 2017. Exposures: Patients were randomized to guselkumab, 100 mg (weeks 0 and 4, then every 8 weeks); placebo followed by guselkumab, 100 mg, starting at week 16; or adalimumab (80 mg [week 0] and 40 mg [week 1, then every 2 weeks]). Main Outcomes and Measures: Efficacy was assessed through week 24. End points included numbers of patients achieving scores of 0 or 1 (clear or near clear) or 0 (clear) on the scalp-specific IGA (ss-IGA), Physician's Global Assessment of the hands and/or feet (hf-PGA), and fingernail PGA (f-PGA) and percentage of improvement in target Nail Psoriasis Severity Index score. Results: Of 1829 randomized patients (mean [SD] age, 43.6 [12.4] years; 1300 [71.1%] male, 1498 [81.9%] white), 1576 (86.2%) had psoriasis of the scalp; 501 (27.4%), palms and/or soles; and 1049 (57.4%), fingernails. At baseline, 1512 (82.7%), 461 (25.2%), and 928 (50.7%) patients had a score of 2 or higher on the ss-IGA, hf-PGA, and f-PGA, respectively, and were included in the analysis. Guselkumab was superior to placebo based on the proportion of patients achieving an ss-IGA score of 0 or 1 (560 [81.8%] vs 43 [12.4%]) at week 16 and to adalimumab (582 [85.0%] vs 329 [68.5%]) at week 24 (both P < .001); 479 (69.9%) in the guselkumab group vs 270 (56.3%) in the adalimumab group achieved an ss-IGA score of 0 (all P < .001). An hf-PGA score of 0 or 1 was achieved by 154 patients (75.5%) in the guselkumab group vs 15 (14.2%) in the placebo group at week 16 and 164 (80.4%) in the guselkumab group vs 91 (60.3%) in the adalimumab group at week 24; 153 (75.0%) in the guselkumab group vs 76 (50.3%) in the adalimumab group achieved an hf-PGA score of 0 (all P < .001). An f-PGA score of 0 or 1 was achieved by 196 patients (46.7%) in the guselkumab group vs 32 (15.2%) in the placebo group at week 16 (P < .001) and 252 (60.0%) in the guselkumab group vs 191 (64.3%) in the adalimumab group at week 24 (P = .11); 115 (27.4%) in the guselkumab group vs 83 (27.9%) in the adalimumab group achieved an f-PGA score of 0 (P = .63). Conclusions and Relevance: Compared with adalimumab, guselkumab was associated with significant improvement in psoriasis on the scalp and palms and/or soles; magnitude of improvement in fingernails did not differ between treatments. These results may help dermatologists make treatment decisions for patients with psoriasis in difficult-to-treat body regions. Trial Registration: ClinicalTrials.gov Identifiers: NCT02207231 and NCT02207244.

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 comparator-controlled VOYAGE 1 trial.

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. 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.

A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis.

BACKGROUND: Little is known about the effect of specific anti-interleukin-23 therapy, as compared with established anti-tumor necrosis factor therapies, for the treatment of moderate-to-severe plaque psoriasis. METHODS: In a 52-week, phase 2, dose-ranging, randomized, double-blind, placebo-controlled, active-comparator trial, we compared guselkumab (CNTO 1959), an anti-interleukin-23 monoclonal antibody, with adalimumab in patients with moderate-to-severe plaque psoriasis. A total of 293 patients were randomly assigned to receive guselkumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter, 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at weeks 0 and 4 and every 12 weeks thereafter) through week 40, placebo, or adalimumab (standard dosage for psoriasis). At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. The primary end point was the proportion of patients with a Physician's Global Assessment (PGA) score of 0 (indicating cleared psoriasis) or 1 (indicating minimal psoriasis) at week 16. RESULTS: At week 16, the proportion of patients with a PGA score of 0 or 1 was significantly higher in each guselkumab group than in the placebo group: 34% in the 5-mg group, 61% in the 15-mg group, 79% in the 50-mg group, 86% in the 100-mg group, and 83% in the 200-mg group, as compared with 7% in the placebo group (P≤0.002 for all comparisons). Moreover, the proportion was significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (58%) (P<0.05 for all comparisons). At week 16, the proportion of patients with at least a 75% improvement in Psoriasis Area and Severity Index scores was significantly higher in each guselkumab group than in the placebo group (P<0.001 for all comparisons). At week 40, the proportion of patients with a PGA score of 0 or 1 remained significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (71%, 77%, and 81%, respectively, vs. 49%) (P<0.05 for all comparisons). Between week 0 and week 16, infections were observed in 20% of the patients in the guselkumab groups, 12% in the adalimumab group, and 14% in the placebo group. CONCLUSIONS: The results of this phase 2 trial suggest that guselkumab may be an effective therapy for plaque psoriasis and that control of psoriasis can be achieved with specific anti-interleukin-23 therapy. (Funded by Janssen Research and Development; X-PLORE ClinicalTrials.gov number, NCT01483599.).

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial.

OBJECTIVE: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. METHODS: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. RESULTS: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. CONCLUSIONS: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS).

BACKGROUND: Available biologic agents for the treatment of psoriasis in China are limited. OBJECTIVES: The LOTUS study is a phase 3, double-blind, placebo-controlled study that evaluated the efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis. PATIENTS AND METHODS: Patients (n=322) were randomized to receive ustekinumab 45 mg or placebo at weeks 0 and 4, with placebo crossover to ustekinumab at week 12; all patients were followed up to week 36. The primary end point was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) at week 12. Other end points at week 12 included the proportion of patients with a Physician's Global Assessment (PGA) score of 0 or 1 and the change in Dermatology Life Quality Index (DLQI) score from baseline. RESULTS: At week 12, 82.5% of ustekinumab-treated patients achieved PASI 75 responses compared with 11.1% of placebo-treated patients (P<.001). Clinical responses were maintained through week 28, with maximum responses observed at week 24. Significant improvements in PGA and DLQI were observed at week 12 and were generally maintained through week 28. At week 12, adverse events rates were similar between groups (45 mg: 42.5% vs placebo: 38.5%), and serious adverse events were reported in 0.6% of patients in each group. Through week 36, no cases of active tuberculosis, serious infections, malignancies, or major adverse cardiovascular events were reported. CONCLUSIONS: Consistent with results previously reported in global phase 3 studies, ustekinumab was highly effective and generally well tolerated in Chinese patients with moderate to severe psoriasis through 36 weeks.

Ustekinumab improves health-related quality of life in Korean and Taiwanese patients with moderate to severe psoriasis: results from the PEARL trial.

BACKGROUND: The PEARL study showed that the proportion of psoriasis patients achieving the primary endpoint (at least 75% improvement from baseline to week 12 in the Psoriasis Area and Severity Index) was significantly higher in ustekinumab-treated patients compared with placebo. There is a paucity of data regarding the impact of psoriasis and its treatment on health-related quality of life (HRQoL) in Asian patients. OBJECTIVES: To evaluate the effect of ustekinumab on HRQoL in Korean/Taiwanese patients with moderate to severe psoriasis enrolled in the phase III, randomized, double-blind, placebo-controlled PEARL study. METHODS: In the PEARL study, 121 patients were randomized to receive ustekinumab 45 mg at weeks 0, 4, and 16 (n=61) or placebo at weeks 0 and 4 with crossover to ustekinumab at weeks 12 and 16 (n=60). A major secondary endpoint was the change in Dermatology Life Quality Index (DLQI) from baseline at week 12. Other endpoints included the change in individual DLQI domains, proportion of patients achieving DLQI ≤ 1 (no negative effect), and proportion of patients achieving ≥ 5-point reduction in DLQI (clinically meaningful improvement) at week 12. RESULTS: At baseline, psoriasis had a very large effect on HRQoL (average DLQI, 15.7). At week 12, patients treated with ustekinumab 45 mg had significantly greater improvement from baseline in DLQI scores compared with placebo (mean decrease, 11.2 vs 0.5 (P<0.001). Likewise, 32.2% and 1.7% of patients receiving ustekinumab 45 mg and placebo, respectively, achieved a DLQI ≤ 1, and 81.4% and 18.3% achieved ≥ 5-point reduction (both P<0.001 vs placebo). Individual DLQI domains in the ustekinumab group were significantly improved compared with placebo (P<0.001). For ustekinumab-randomized patients, HRQoL improvements were sustained through week 28. Placebo patients who crossed over to ustekinumab experienced similar improvements compared with those randomized to ustekinumab. CONCLUSIONS: Ustekinumab significantly improves HRQoL in Korean/Taiwanese patients with moderate to severe psoriasis.

Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: a randomized, placebo-controlled, phase II trial.

OBJECTIVE: To use data from a phase II clinical trial to evaluate the effect of ustekinumab, a human immunoglobulin monoclonal antibody that binds with high affinity to the shared p40 subunit of human interleukins-12 and -23, on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). METHODS: In this multicenter, double-blind, placebo-controlled, crossover study of ustekinumab, patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70). Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients. HRQoL was evaluated using the Dermatology Life Quality Index (DLQI) in a subset of patients (84.9%) with at least 3% body surface area (BSA) psoriasis involvement at baseline. RESULTS: At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL. At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (-0.31) and DLQI (-8.6) scores versus placebo (-0.04 and -0.8, respectively; p < 0.001 for both comparisons). At week 12, 58.7% (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5% (3/55) for placebo (p < 0.001). The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo. Potential limitations of the study include the short duration of the placebo-controlled period and the relatively small patient population. CONCLUSION: Ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3% BSA.

Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension.

OBJECTIVE: To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). METHODS: Patients eligible for the open-label extension (OLE, weeks 52-204) received infliximab 3-6 mg/kg every 8 weeks plus methotrexate. RESULTS: Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. CONCLUSIONS: In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.