Guselkumab for the Treatment of Psoriasis

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1 BioDrugs REVIEW ARTICLE Guselkumab for the Treatment of Psoriasis Álvaro Machado 1 Tiago Torres 1,2,3 Ó Springer International Publishing AG, part of Springer Nature 2018 Abstract Psoriasis is a common, chronic, immune-mediated, inflammatory skin disease with systemic involvement and significant impact on patients quality of life. Several biologic treatments have been developed in recent decades, such as tumor necrosis factor (TNF)-a inhibitors, a nonselective interleukin (IL)-23 inhibitor (ustekinumab, which also inhibits IL-12), and most recently IL-17 inhibitors. Guselkumab is a novel biological therapy that selectively targets IL-23 and is the first-in-class selective IL-23 inhibitor approved to treat moderate-to-severe plaque psoriasis. These inhibitors are expected to have some advantages over the highly effective IL-17 inhibitors, as they do not worsen inflammatory bowel disease and are not involved in the development of candida infections. Additionally, selective inhibition of IL-23 may have additional benefits over ustekinumab as the IL-12-dependent cascades remain functional. These benefits include a decrease in IL-17Aproducing T cells in the skin and the promotion of an antiinflammatory effect through production of interferon-c and IL-10. In terms of efficacy, guselkumab showed promising results in the treatment of psoriasis and psoriatic arthritis, although it did not show significant clinical improvement in rheumatoid arthritis. Studies in other inflammatory diseases and Crohn s disease are expected to begin soon. Overall, guselkumab was well tolerated; the most common & Tiago Torres torres.tiago@outlook.com Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal Dermatology Research Unit, Centro Hospitalar do Porto, Porto, Portugal adverse event was nasopharyngitis. Head-to-head studies comparing IL-23 inhibitors with agents in different classes, namely IL-17 inhibitors, will be crucial to establish the true role of these agents in psoriasis treatment. Key Points The interleukin (IL)-23/17 axis is currently considered essential in the pathogenesis of psoriasis. Selective inhibition of IL-23 may have several advantages over the combined inhibition of IL-23 and IL-12, as IL-12-dependent functions remain intact. Guselkumab is the first in its class to be approved to treat moderate-to-severe plaque psoriasis and has a convenient dosing regimen and excellent safety profile. 1 Introduction Psoriasis is a common, chronic, immune-mediated and inflammatory skin disease with systemic involvement and significant impact on patients quality of life [1, 2]. It has an estimated prevalence that ranges from 1 to 8.5% in the population and an incidence between 78.9 and 230 per 100,000 person-years [2]. Psoriasis treatment evolved immensely over the last decades as knowledge about the disease s pathophysiology became clearer. In the 1950s, the treatment of

2 Á. Machado, T. Torres inflammatory dermatoses, including psoriasis, was redefined when hydrocortisone showed promising results [3]. Later, cyclosporine proved to be an effective treatment for psoriasis, emphasizing the importance of the immune system, namely T cells. Thus, further studies focused on the immune-mediated mechanisms that could be involved in psoriasis pathophysiology [4, 5]. The development of biologic therapies completely transformed the care of patients with moderate to severe psoriasis. The emergence of tumor necrosis factor (TNF)-a inhibitors was perhaps the first big step, as significantly higher clinical responses were achieved. Additionally, the success of this approach highlighted the importance of TNF-a in the physiopathogenesis of psoriasis. However, some patients did not respond to such agents, which led to further investigation of additional and possibly more crucial targets. Later, ustekinumab, an interleukin (IL)-12/23 inhibitor that blocks the common p40 subunit of these cytokines, was developed after the p40 subunit was shown to be increased in psoriasis plaques [6]. Subsequent studies showed not only significant improvement in clinical responses [7] but also better responses than with TNF-a inhibitors [8]. Recently, new classes of agents have gained increasing relevance IL-17 receptor inhibitors (e.g., brodalumab) and IL-17 inhibitors (secukinumab and ixekizumab). These agents have been approved to treat moderate to severe psoriasis [9 11] and have shown high levels of sustained efficacy and better clinical responses than TNF-a inhibitors [12, 13] and ustekinumab [10, 14, 15]. A new class of drugs is now being studied and developed in the treatment of psoriasis: IL-23 inhibitors. Guselkumab is a fully human immunoglobulin G1-lambda (IgG1k) monoclonal antibody that selectively targets the unique p19 subunit of human IL-23 without binding IL-12 [16 20] and was approved by the US FDA in July 2017 [21] and by the European Medicines Agency in September 2017 [22] for the treatment of moderate-to-severe plaque psoriasis. Tildrakizumab may also be available soon, whereas risankizumab is in a late stage of development and LY is still under investigation (NCT ) [23]. This article aims to review the current knowledge on selective IL-23 inhibition in psoriasis, focusing on guselkumab. 2 Advantages of Selective Inhibition of Interleukin (IL)-23 Although ustekinumab proved effective in the treatment of psoriasis, evidence has suggested a more important role of IL-23 in psoriasis pathogenesis compared with IL-12. IL- 23 is composed of two subunits p40, shared with IL-12, and a unique p19 subunit. In fact, it has been shown that the p40 subunit, but not the p35 subunit, which is exclusive of IL-12, is increased in lesional psoriatic skin. Furthermore, the IL-23/-17 axis has been reported to be essential in psoriasis pathogenesis, being involved in the differentiation of naive T cells into IL-17-producing T cells [24 26] (Fig. 1). Interestingly, inhibition of IL-12 may have a negative effect in psoriasis [27]. Several mechanisms have been suggested, including a regulatory function of IL-12 inhibiting the infiltration of IL-17A-producing cdt cells and inducting a protective transcriptional program in keratinocytes, thus limiting skin inflammation, as demonstrated in an imiquimod murine model [28]. Also, mice lacking the IL-12-specific receptor subunit developed more severe lesions [27]. Additionally, IL-12 has an anti-inflammatory effect through induction of expression of IL-10 by type 1 T-helper (Th1) cells, in which interferon (IFN)-c is a crucial mediator [29]. In fact, IL-10 plays a pivotal role in the maintenance of tolerance and limitation of immunemediated processes, as shown in IL-10-deficient mice that developed chronic intestinal inflammation due to an uncontrolled immune reaction against intestinal flora [30]. Finally, IL-12 has been implicated in the protection against bacterial and viral infections [31] and may have a role in tumor immune surveillance through regulation of both innate (natural killer cells) and adaptive (cytotoxic T lymphocytes) immune responses [32, 33]. 3 Guselkumab 3.1 Pharmacokinetics A phase I randomized study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of guselkumab administered as a single intravenous ( mg/ kg) or subcutaneous ( mg) dose [34]. Investigators observed that mean maximum serum concentration and area under the zero-to-infinity serum concentration time curve values increased in an approximately dose-proportional manner. Mean clearance and volume of distribution ranged from 3.62 to 6.03 ml/day/kg and from to ml/kg, respectively. The mean half-life ranged from 12 to 19 days when administered intravenously and from 15 to 17 days following subcutaneous administration [34]. A phase II study assessed the efficacy and safety of subcutaneous guselkumab (50 and 200 mg at weeks 0 and 4 and every 8 weeks, through week 28) with ustekinumab in patients with rheumatoid arthritis [35] and reported that median trough serum levels of guselkumab reached a

3 Guselkumab for Psoriasis Fig. 1 Summarized schematic differences between IL-12/23, selective IL-23, and IL-17 inhibition. Non-selective IL-23 inhibitors such as ustekinumab block IL-12 and IL-23 common subunit p40, inhibiting both the IL-23/T17 and the IL-12/Th1 pathways. Selective IL-23 inhibitors such as guselkumab, tildrakizumab, and risankizumab selectively block the IL-23/T17 pathway, avoiding effects on the steady state by week 20 and were maintained through week Clinical Efficacy in Psoriasis Phase I Studies A phase I first-in-human, randomized, double-blind, placebo-controlled trial, which included 24 patients with moderate-to-severe plaque psoriasis, assessed the clinical response to and tolerability and safety of subcutaneous injections (10, 30, 100, and 300 mg) of guselkumab [36]. At week 12 (primary endpoint), Psoriasis Area and Severity Index (PASI) 75 was 50% for 10 mg, 60% for 30 and 100 mg, and 100% for 300 mg. Additionally, at week 12, PASI 90 was achieved in 25, 40, 0, and 80% of patients receiving 10, 30, 100, and 300 mg, respectively. These PASI scores were generally maintained through week 24 in all treated groups, except those receiving 100 mg, in whom the initial high levels of response were lost over the followup. Physician Global Assessment (PGA) scores were generally consistent with PASI responses over time. Investigators also performed histologic and gene expression analysis and found a significant reduction in the epidermal thickness and in T cell and dendritic cell counts in guselkumab-treated patients compared with those receiving placebo. Furthermore, significant reductions and IL-12/Th1 axis. IL-17A inhibitors such as secukinumab and ixekizumab also target the IL-23/IL-17 axis but via downstream blockade of this pathway. DC dendritic cell, IL interleukin, KC keratinocyte, Th T-helper cell Adapted from Torres [5], with permission normalization of psoriasis-related gene expression and serum IL-17 levels were observed [36] Phase II Studies A phase II 52-week, dose-ranging, randomized, doubleblind, placebo-controlled, active-comparator trial compared guselkumab with adalimumab in patients with moderate-to-severe psoriasis [18]. In total, 293 patients were randomized to placebo, five guselkumab groups (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, or adalimumab in the standard psoriasis dosing regimen. At week 16, the proportion of patients achieving a PGA score of 0 or 1 (primary endpoint) was significantly higher with all guselkumab doses than with placebo (34% with 5 mg, 61% with 15 mg, 79% with 50 mg, 86% with 100 mg, and 83% with 200 mg). Additionally, those receiving guselkumab 50 mg, 100 mg, or 200 mg had significantly higher PGA scores of 0 or 1 (p\0.05) than those in the adalimumab group. A dose-proportional response was noted for the lowest dose groups, whereas results were similar between patients receiving 100 and 200 mg. PASI 75, 90, and 100 scores were significantly higher in guselkumab-treated groups than in the placebo group. Specifically, all guselkumab groups, except those

4 Á. Machado, T. Torres receiving 5 mg, had PASI 75 scores of at least 75%. Interestingly, clinical responses (PGA score of 0 or 1 and PASI 75) were observed as early as week 4. From week 16 to week 40, an increased number of patients with a PGA score of 0 or 1 was observed (maximum response at week 20), and these responses were generally maintained from week 24 to week 40. PASI scores showed a similar pattern over time. Compared with those receiving adalimumab, guselkumab-treated groups (except for the 5-mg group) had a higher proportion of patients achieving PGA scores of 0 or 1, with significant differences observed in the 50-mg (20% points), 100-mg (28% points), and 200-mg (25% points) groups. These differences were also significant at week 40: 71% for 50 mg, 77% for 100 mg, and 81% for 200 mg versus 49% for adalimumab. At week 16, PASI 75 scores were achieved by 44% with 5 mg, 76% with 15 mg, 81% with 50 mg, 79% with 100 mg, and 81% with 200 mg, whereas the response with adalimumab was 70%. The statistical significance of these results was not reported Phase III Studies VOYAGE 1 was a phase III randomized, double-blind, placebo-controlled (from week 0 to week 16, after which patients crossed over to receive guselkumab through week 48), active-controlled trial comparing guselkumab with adalimumab from week 0 to week 48 [16]. Patients were randomized 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. Guselkumab was superior to placebo and adalimumab when assessing the proportion of patients achieving an Investigator s Global Assessment (IGA) score of 0/1 and PASI 90 (coprimary endpoints) and all major secondary endpoints. At week 16, significantly higher proportions of patients achieved IGA 0/1 (85.1 vs. 6.9% in the placebo group) and PASI 90 (73.3 vs. 2.9% in the placebo group). In addition, significantly higher proportions of patients achieving IGA, PASI 75, and PASI 100 were also observed (Table 1). When compared with adalimumab at week 16, guselkumab-treated patients also had significantly higher IGA 0/1 (85.1 vs. 65.9%), PASI 90 (73.3 vs. 49.7%), and PASI 75 (91.2 vs. 73.1%) scores. Responses were still significantly different at week 24 (IGA 0/1 for 84.2 vs. 61.7%; PASI 90 for 80.2 vs. 53%) and at week 48 (IGA 0/1 for 80.5 vs. 55.4%; PASI 90 for 76.3 vs. 47.9%). After initiating guselkumab, at week 16, patients in the placebo cross-over group achieved similar responses to those in the guselkumab group. In this study, regional psoriasis was also assessed using scalp-specific IGA, fingernail PGA (f-pga), Nail Psoriasis Severity Index (NAPSI), and PGA of the hands and/or feet. At week 16, a significantly higher proportion of guselkumab-treated patients achieved scalp-specific IGA 0/1 compared with placebo (83.4 vs. 14.5%) and at weeks 24 and 48 guselkumab showed significantly better results than did adalimumab. Additionally, at week 16, a significantly higher proportion of guselkumab-treated patients had an f-pga 0/1 and percent improvement in NAPSI score compared with placebo. When compared with adalimumab, although results in f-pga were comparable at week 24, significant differences were observed at week 48. On the other hand, NAPSI scores were comparable between guselkumab and adalimumab at weeks 24 and 48. The proportion of patients achieving PGA 0/1 of the hands and/or feet was significantly higher in guselkumab-treated patients than in those receiving placebo at week 16 (73.3 vs. 14.0%), and responses were superior to adalimumab at weeks 24 (78.9 vs. 56.8%; p\0.001) and 48 (75.6 vs. 62.1%; p\0.045). Finally, investigators also evaluated health-related quality of life with patient-reported outcomes using the Dermatology Life Quality Index (DLQI) and the Psoriasis Symptoms and Signs Diary (PSSD). At week 16, significant differences were observed in the proportions of guselkumab-treated patients with an improvement from baseline DLQI and an achievement of DLQI score 0/1 compared with placebo. Additionally, at weeks 24 and 48, guselkumab showed significantly better results than did adalimumab for both improvements from baseline DLQI score and achievement of DLQI 0/1. Regarding PSSD, at week 16, guselkumab showed significantly better results versus placebo for both PSSD symptom score and mean changes in PSSD sign score. Similarly, at weeks 24 and 48, mean changes in PSSD scores were significantly better for guselkumab than for adalimumab. In VOYAGE 2, a complementary study of VOYAGE 1, investigators assessed the efficacy and safety of interrupted treatment in responders (patients who achieved at least PASI 90), which included a randomized withdrawal and retreatment period from weeks 28 to 72 (data only from weeks 28 to 48 were shown) [20]. VOYAGE 2 confirmed the results of VOYAGE 1 relating to efficacy of guselkumab versus both placebo and adalimumab, as similar results were observed. Concerning the randomized and retreatment period, PASI 90 responses were better maintained in patients continuing guselkumab than in responders re-randomized to placebo. Through week 48, a total of 88.6% of patients continuing guselkumab sustained a PASI 90 response compared with 36.8% in the withdrawal group. Similar results were observed in improvements in DLQI and PSSD scores. Lastly, when assessing adalimumab nonresponders who switched to guselkumab, PASI 90 and

5 Guselkumab for Psoriasis Table 1 Summary of key results from clinical trials of guselkumab Clinical trial Dosing regimen Proportion of pts achieving PASI 75 PASI 90 PASI 100 IGA 0/1 VOYAGE mg at wk 0, 4 and every 8 wk 91.2%, ADA 73.1%, PL 5.7% 91.2%, ADA 72.2% At wk 48: GUS 87.8%, ADA 62.6% VOYAGE %, ADA 68.5%, PL 8.1% 89.1%, ADA 71.0% NAVIGATE In pts with inadequate response to NR UST: 100 mg at wk 0, 4 and every 8 wk 73.3%, ADA 49.7%, PL 2.9% 80.2%, ADA 53.0% At wk 48: GUS 76.3%, ADA 47.9% 37.4%, ADA 17.1%, PL 0.6% 44.4%, ADA 24.9% At wk 48: GUS 47.4%, ADA 23.4% 85.1%, ADA 65.9%, PL 6.9% 84.2%, ADA 61.7% At wk 48: GUS 80.5%, ADA 55.4% 70.0%, ADA 46.8%, PL 2.4% 75.2%, ADA 54.8% 34.1%, ADA 20.6%, PL 0.8% 44.2%, ADA 26.6% 84.1%, ADA 67.7%, PL 8.5% 83.5%, ADA 64.9% At wk 28: GUS 48.1%, UST 22.6% (p\0.001) At wk 52: GUS 51.1%, UST 24.1% (p\0.001) At wk 28: NR At wk 52: GUS 20.0%, UST 7.5% (p = 0.003) At wk 28: GUS 31.1%, UST 14.3% (p = 0.001) At wk 52: GUS 36.3%, UST 17.3% (p\0.001) Non-responder imputation was used to assess binary endpoint missing data ADA adalimumab, GUS guselkumab, NR not reported, PL placebo, pts patient(s), UST ustekinumab, wk week(s) PASI 100 response rates were higher after switching, at 66.1 and 28.6%, respectively, at week 48. Recently, a study evaluated the consistency of efficacy of guselkumab across several subpopulations of patients with psoriasis using pooled data from VOYAGE 1 and VOYAGE 2 trials [37]. Subgroups were defined by baseline demographics, psoriasis disease characteristics, and previous psoriasis treatments. Guselkumab provided significant benefit across almost all subpopulations, as greater proportions of patients achieved IGA 0/1 compared with placebo at week 16 and compared with adalimumab at week 24. Of note, guselkumab showed a more consistent response among lighter and heavier patients when comparing with adalimumab. Finally, NAVIGATE was a phase III, randomized, double-blind study assessing the clinical efficacy of guselkumab in patients with moderate to severe psoriasis and inadequate response to ustekinumab. A total of 871 patients received ustekinumab (45 or 90 mg) at weeks 0 and 4 [19]. At week 16, patients with inadequate response to ustekinumab (IGA C 2) were randomized to guselkumab 100 mg at weeks 16, 20, and every 8 weeks or to continue ustekinumab at week 16 and every 12 weeks thereafter. The primary endpoint was the number of visits at which randomized patients achieved IGA 0/1 and C 2-grade improvement relative to week 16 from week 28 through week 40. PASI 90, PASI 100, and DLQI of 0/1 were also evaluated. The mean number of visits at which patients had an IGA 0/1 and C 2-grade improvement (week 28 40) was significantly greater in the guselkumab group than in the randomized ustekinumab group. Additionally, significantly more patients achieved IGA 0/1 and C 2-grade improvement at week 28 and week 52. Finally, greater proportions of patients in the guselkumab group achieved PASI 90, PASI 100, and DLQI 0/1 compared with ustekinumabtreated patients at week 52 (Table 1). To conclude, in NAVIGATE, patients with inadequate response to ustekinumab significantly benefited from switching to guselkumab. 3.3 Clinical Efficacy in Psoriatic Arthritis Psoriatic arthritis (PsA), a psoriasis-related spondyloarthropathy, may develop in 20 30% of patients with psoriasis [38]. The utility of guselkumab in the treatment of patients with PsA was also evaluated. In a phase IIa

6 Á. Machado, T. Torres randomized, double-blind, placebo-controlled multicentre study, all primary and all secondary endpoints were met, as guselkumab demonstrated significant improvement in joint symptoms, physical function, enthesitis, dactylitis, and quality of life [39]. Two phase III trials are underway to investigate the efficacy and safety of guselkumab in patients with PsA, one of them including patients previously treated with TNF-a inhibitors (NCT ; NCT ). 3.4 Clinical Efficacy in Other Indications The efficacy of guselkumab was also evaluated in patients with rheumatoid arthritis in a phase II randomized, doubleblind, placebo-controlled trial investigating the efficacy and safety of guselkumab and ustekinumab in patients with active rheumatoid arthritis despite treatment with methotrexate [37]. Guselkumab and ustekinumab did not significantly reduce the signs and symptoms of rheumatoid arthritis, as there were no statistically significant differences in the proportions of patients achieving an American College of Rheumatology (ACR)-20 response between guselkumab and ustekinumab groups compared with the placebo group [37]. Currently, there are no ongoing studies evaluating guselkumab in patients with rheumatoid arthritis. To date, no studies are evaluating guselkumab in Crohn s disease. However, given the efficacy of ustekinumab in these patients, guselkumab will likely enter clinical trials soon [40]. 3.5 Safety and Tolerability A phase I study reported comparable adverse event (AE) rates between guselkumab and placebo groups (65 vs. 50%, respectively) and reported no serious AEs [36]. In a phase II study, at week 16, the incidence of AEs was similar between groups (50% in the guselkumab groups, 56% in the adalimumab group, and 52% in the placebo group) [18]. Specifically, the most commonly reported AE was infection, with rates of 20% in the guselkumab groups, 12% in the adalimumab group, and 14% in the placebo group. A serous AE was reported in two patients in the guselkumab 50 mg group (lung abscess and appendicitis). From week 16 to 52, the AE rates in the guselkumab groups was 49% compared with 61% in the adalimumab group. As in the first 16 weeks, the most frequent AE was infection, which was observed in roughly 30% of patients. No infection-related serious AEs were reported in the guselkumab groups. Of note, no cases of tuberculosis or opportunistic infections were reported. Major adverse cardiac events (MACEs) were also reported, as one patient died from myocardial infarction in the guselkumab 5-mg group and two patients in the 100-mg group experienced nonfatal myocardial infarction and stroke. Lastly, one case of cancer (grade 3 cervical intraepithelial neoplasia) was reported in a patient receiving guselkumab. Throughout the whole study, there was no evidence of a relationship between the dose and the rate of AEs among the guselkumab groups. In the phase II study assessing the efficacy and safety of guselkumab with ustekinumab in patients with rheumatoid arthritis [35], the proportions of patients with at least one AE were comparable among the treatment groups. Infections were the most common AE, and no evident differences were observed between treatment groups. No cases of tuberculosis or opportunistic infections were observed. All serious AEs reported were isolated and no association between the events and the active treatments was noted. VOYAGE 1 investigators also reported comparable AEs between treatment groups and throughout the study. The most frequent events were nasopharyngitis and upper respiratory tract infection [16]. Treatment withdrawal due to AEs was infrequent and similar between the groups. Isolated events also occurred: at week 16, one case of basal cell carcinoma in the guselkumab group and two MACEs (one in each of the guselkumab and adalimumab groups). From week 16 to week 48, two serious infections were reported in the guselkumab group (thigh abscess and cellulitis) and another two in the adalimumab group (abdominal abscess and a fatal staphylococcal pneumonia). Additionally, two other basal cell carcinomas were reported, one each in the guselkumab and adalimumab groups, and two malignancies prostate and breast in the guselkumab group. Of note, the incidence of candidiasis and neutropenia was low and comparable between groups. No Crohn s disease-related events were noted. Laboratory abnormalities were low and similar between groups. VOYAGE 2 confirmed the results of VOYAGE 1, as the proportions of patients with AEs, AEs leading to discontinuation, and serious AEs were comparable in the first 16 weeks of the study (placebo-controlled period) [20]. Headache was added to the list of the most common events, along with nasopharyngitis and upper respiratory tract infection. Unlike in VOYAGE 1, no malignancies or nonmelanoma skin cancers (NMSCs) were observed in this period. One case of MACE occurred in the adalimumab group. In the active-comparator period (weeks 0 28), the pattern of AEs observed was similar to that in the placebocontrolled period. Three serious infections were observed in the guselkumab group (bronchitis, erysipelas, and softtissue infection), and another three were reported in the adalimumab group (two cases of tuberculosis and one injection-site abscess). One malignancy (prostate cancer) and two NMSCs (one squamous cell carcinoma in the guselkumab group and one basal cell carcinoma in the

7 Guselkumab for Psoriasis placebo/guselkumab group) were reported. Two cases of MACE were observed, one each in the guselkumab and the adalimumab group. In the randomized withdrawal and retreatment period (weeks 28 48), one serious infection was reported (appendicitis) in the maintenance group. From weeks 28 to 48, one case of MACE was reported in the placebo guselkumab group, and, through week 48, one basal cell carcinoma and one squamous cell carcinoma were also reported in the placebo guselkumab group. No other events were observed. Finally, as in VOYAGE 1, laboratory abnormalities were low and comparable between groups. In terms of the safety profile in patients with psoriatic arthritis and rheumatoid arthritis, guselkumab was also well tolerated, and no new AEs were observed. 3.6 Immunogenicity Gordon et al. [18] reported antibodies to guselkumab in 6% of patients, albeit non-neutralizing and with low titers. In the phase II study comparing guselkumab and ustekinumab in patients with rheumatoid arthritis [35], 11.3% of guselkumab-treated patients had positive antibodies to guselkumab, but again, they were non-neutralizing as the serum guselkumab concentrations were similar between patients who tested positive and those who tested negative for antibodies. In part 2 of the study by Zhuang et al. [34], which included patients with psoriasis, 1 of 20 patients (5.0%) had positive antibodies to guselkumab. Information about guselkumab clearance and elimination half-life (t ) was not reported [34]. VOYAGE 1 and 2 reported rates of antibody development of 5.3% through week 44 and 6.6% through week 48, respectively. No association between antibody incidence and reduced efficacy was noted [16, 20]. 4 Other p19 Inhibitors 4.1 Tildrakizumab Tildrakizumab is an IgG1j monoclonal antibody, the efficacy of which in treating moderate to severe plaque psoriasis has been shown in phase II and III studies [41, 42]. In resurface 1, a phase III RCT, patients were randomized to tildrakizumab 200 mg (n = 308), tildrakizumab 100 mg (n = 309), or placebo (n = 155). In the second phase III RCT, resurface 2, patients were randomized to tildrakizumab 200 mg (n = 314), tildrakizumab 100 mg (n = 307), etanercept 50 mg (n = 313), or placebo (n = 156). Tildrakizumab was administered at baseline and week 4 and subsequently every 12 weeks in both trials. Week 12 results from resurface 1 showed that 62% of the patients receiving 200 mg and 64% of those receiving 100 mg achieved PASI 75 compared with 6% receiving placebo and that 59% of those receiving 200 mg and 58% of those receiving 100 mg achieved PGA responses compared with 7% receiving placebo. In resu- FARCE 2, 66% in the 200-mg group and 61% in the 100-mg group achieved PASI 75 compared with 48% in the etanercept group and 6% in the placebo group. Furthermore, 59% of patients in the 200-mg group and 55% in the 100-mg group achieved PGA responses compared with 4% in the placebo group and 48% in the etanercept group [42]. In terms of safety and tolerability, tildrakizumab was well tolerated overall, with the most common adverse event being nasopharyngitis. Treatment-related discontinuations were infrequent [42]. 4.2 Risankizumab Risankizumab is an IgG1j monoclonal antibody that showed promising results in a phase II dose-ranging randomized trial. The study investigated risankizumab compared with ustekinumab in 166 patients with moderate-tosevere psoriasis [43]. Patients were randomly assigned to risankizumab (single 18-mg dose at week 0 or doses of 90 mg or 180 mg at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). Risankizumab was superior to ustekinumab: 77% of patients receiving risankizumab (90 and 180 mg pooled) achieved a PASI 90 or greater response at week 12 (primary endpoint) compared with 40% of ustekinumab-treated patients. Additionally, at week 12, totals of 63, 98, and 88% of patients receiving risankizumab achieved PASI 75 in the 18-, 90-, and 180-mg dose groups, respectively, compared with 72% of ustekinumab-treated patients. PASI 100 responses were observed in 14, 41, and 48% of those receiving risankizumab 18, 90, and 180 mg, respectively, compared with 18% of the ustekinumab group. Furthermore, at week 24, the proportion of patients who achieved a PASI 75 response was 53, 90, and 88% in those receiving risankizumab 18, 90, and 180 mg, respectively, compared with 70% of the ustekinumab group. Additionally, 28, 63, and 81% of risankizumab-treated patients (18, 90, and 180 mg, respectively) achieved PASI 90 at week 24 compared with 55% of those in the ustekinumab group. Interestingly, improvements in PASI score were observed as early as week 2. Risankizumab was also well tolerated: rates of reported side effects were similar in the treatment and placebo groups. The most common AE was nasopharyngitis [43]. Recently, a press release has revealed promising results from phase III clinical trials with 12-week dosing regimens. Results of two replicate studies ultimma-1 and ultimma-2 showed that risankizumab achieved

8 Á. Machado, T. Torres significantly greater responses of clear or almost clear skin (static PGA [spga] 0/1) than did ustekinumab and adalimumab, with rates ranging from 84 to 88% at week 16. Also, at 1 year, 56 and 60% of patients treated with risankizumab achieved PASI 100 compared with 21 and 30% with ustekinumab [44]. Peer reviewed study results are expected soon. Finally, in a recent phase II study in patients with active Crohn s disease, risankizumab was more effective than placebo at inducing clinical remission. Thus, selective inhibition of IL-23 might be a viable therapeutic approach in these patients [5, 45]. 5 Discussion Currently, the IL-23/IL-17 axis is widely considered the most important pathogenic pathway in psoriasis. The clinical efficacy of IL-23p19 and IL-17 inhibitors reinforce this concept. Although some IL-23p19 inhibitors are in a late stage of development, IL-17 inhibitors are already approved and used to treat moderate-to-severe psoriasis. These two drug classes differ in some aspects. Specifically, IL-17 inhibitors were ineffective in the treatment of inflammatory bowel disease, with a tendency to worsen the disease [46, 47]. Furthermore, IL-17 is crucial in the immune response against Candida infections. However, although Candida infections have been reported, the majority were mild to moderate in severity and resolved with conventional therapy, and some experts do not consider these infections a reason to discontinue IL-17 inhibitor treatment [48]. Selective IL-23 inhibition may prove to have great benefit, as IL-12-dependent funtions remain intact. In fact, IL-12 has been associated with inhibition of infiltration of IL-17A-producing cdt cells in the skin, which is a key cytokine in psoriasis pathogenesis [27]. IL-12 may also have anti-inflammatory properties that increase the expression of IL-10 through IFN-c, which may result in a synergic effect in decreasing psoriasis inflammation [29]. Guselkumab is the first in its class to be approved to treat moderate-to-severe plaque psoriasis [21]. Tildrakizumab may also be available soon. Although no head-tohead comparison has been performed, tildrakizumab appears to show numerically inferior efficacy. Results of only phase II studies are available for risankizumab; although these were promising and better than for guselkumab and tildrakizumab, phase III studies will establish the true efficacy of this agent. Dosing regimen is also important and can be a decisive factor since recent treatment options tend to be highly effective, with most patients achieving almost clear or clear skin. The dosing regimens of tildrakizumab and risankizumab are similar every 12 weeks compared with guselkumab, which is administered every 8 weeks, in the maintenance period. Although guselkumab is administered more often, we believe the dosing regimen is still convenient; if guselkumab proves the most effective in the class, administration frequency may become less important. Safety and immunogenicity results were similar: Overall, all three agents were welltolerated, and AEs were mild to moderate, with infections namely nasopharyngitis being the most common. Future studies with more patients and longer follow-up periods will help establish a more complete safety profile for these agents. As discussed, guselkumab has not been studied in populations with Crohn s disease. However, given the efficacy of risankizumab in this disease [5, 45], guselkumab is expected to enter clinical trials assessing its efficacy in this regard soon. A recent Cochrane meta-analysis showed that, compared with placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis, although head-to-head trials are essential to establish the true role of these agents in psoriasis treatment [49]. Interestingly, the first study to compare guselkumab with an agent from a different class secukinumab, an IL-17A inhibitor is ongoing (ECLIPSE NCT ). Furthermore, two ongoing studies are assessing the efficacy of guselkumab in the treatment of generalized pustular psoriasis or erythrodermic psoriasis (NCT ) and palmoplantar pustulosis (NCT ). Guselkumab may also be an option in specific situations. Results from NAVIGATE were interesting, with guselkumab being effective in patients with an inadequate response to ustekinumab. Although why remains unclear, potential reasons include a more potent blockade of IL-23 with guselkumab and/or increased Th17 responses with ustekinumab [19]. Finally, guselkumab might be a good alternative in patients who do not respond to TNF-a inhibitors and ustekinumab, as shown in VOYAGE 2 and NAVIGATE [19, 20]. Real-world results will be crucial in unveiling the role of guselkumab in psoriasis treatment, as the disease is often difficult to treat and has frequently already been treated with multiple biological drugs. 6 Conclusion Guselkumab is a monoclonal antibody that selectively targets IL-23 and is the first in its class to be approved to treat moderate-to-severe plaque psoriasis. Its very effective and safe profile combined with a convenient dosing

9 Guselkumab for Psoriasis regimen could see it soon considered as first-line treatment for moderate-to-severe psoriasis. Funding No sources of funding were used to conduct this study or prepare this manuscript. Compliance with ethical standards Conflicts of interest Álvaro Machado has no conflicts of interest. Tiago Torres has participated in clinical trials sponsored by AbbVie, Amgen, and Novartis and has received honoraria for acting as a consultant and/or as a speaker at events sponsored by AbbVie, Boehringer Ingelheim, Celgene, Janssen, Leo-Pharma, Lilly-Eli, MSD, Novartis, and Pfizer. References 1. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3): Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2): Sulzberger MB, Witten VH. The effect of topically applied compound F in selected dermatoses. J Invest Dermatol. 1952;19(2): Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979;301(10): Torres T. Selective interleukin-23 p19 Inhibition: another game changer in psoriasis? Focus on Risankizumab. Drugs. 2017;77(14): Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006;176(3): Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625): Strober BE, Bissonnette R, Fiorentino D, Kimball AB, Naldi L, Shear NH, et al. Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]). J Am Acad Dermatol. 2016;74(5): e4. 9. Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4): e Thaçi D, Blauvelt A, Reich K, Tsai T-F, Vanaclocha F, Kingo K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73(3): Puig L. Brodalumab: the first anti-il-17 receptor agent for psoriasis. Drugs Today. 2017;53(5): Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CEM, Papp K, et al. Secukinumab in plaque psoriasis results of two phase 3 trials. N Engl J Med. 2014;371(4): Griffiths CEM, Reich K, Lebwohl M, Van De Kerkhof P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993): Reich K, Pinter A, Lacour JP, Ferrandiz C, Micali G, French LE, et al. Comparison of ixekizumab with ustekinumab in moderateto-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177(4): Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14): Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen Y-K, et al. 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. J Am Acad Dermatol. 2017;76(3): Fragoulis GE, Siebert S, Mcinnes IB. Therapeutic targeting of IL- 17 and IL-23 cytokines in immune-mediated diseases. Annu Rev Med. 2016;67: Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, et al. A Phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373(2): Langley RG, Tsai T-F, Flavin S, Song M, Randazzo B, Wasfi Y, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase 3 NAVIGATE trial. Br J Dermatol. 2017;38(1): Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOY- AGE 2 trial. J Am Acad Dermatol. 2017;76(3): Markham A. Guselkumab: first global approval. Drugs. 2017;74(13): Ault A. Guselkumab (Tremfya) Gets CHMP Backing for Plaque Psoriasis Accessed Jan Tonini A, Gualtieri B, Panduri S, Romanelli M, Chiricozzi A. A new class of biologic agents facing the therapeutic paradigm in psoriasis: anti-il-23 agents. Expert Opin Biol Ther. 2017;6: Chiricozzi A, Saraceno R, Chimenti MS, Guttman-Yassky E, Krueger JG. Role of IL-23 in the pathogenesis of psoriasis: a novel potential therapeutic target? Expert Opin Ther Targets. 2014;18(5): Girolomoni G, Strohal R, Puig L, Bachelez H, Barker J, Boehncke WH, et al. The role of IL-23 and the IL-23/T H 17 immune axis in the pathogenesis and treatment of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(10): Chiricozzi A, Romanelli P, Volpe E, Borsellino G, Romanelli M. Scanning the Immunopathogenesis of Psoriasis. Int J Mol Sci. 2018;19(1): Kulig P, Musiol S, Freiberger SN, Schreiner B, Gyülveszi G, Russo G, et al. IL-12 protects from psoriasiform skin inflammation. Nat Commun. 2016;28(7): van der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182(9): Chang HD, Radbruch A. The pro- and anti-inflammatory potential of interleukin-12. Ann N Y Acad Sci. 2007;1109(30):40 6.

10 Á. Machado, T. Torres 30. Kim J, Krueger JG. The Immunopathogenesis of Psoriasis. Dermatol Clin. 2015;33(1): Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci. 2010;11(3): Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol. 1998;16(1): Lu X. Impact of IL-12 in cancer. Curr Cancer Drug Targets. 2017;17(8): Zhuang Y, Calderon C, Marciniak SJ, Bouman-Thio E, Szapary P, Yang TY, et al. First-in-human study to assess guselkumab (anti-il-23 mab) pharmacokinetics/safety in healthy subjects and patients with moderate-to-severe psoriasis. Eur J Clin Pharmacol. 2016;72(11): Smolen JS, Agarwal SK, Ilivanova E, Xu XL, Miao Y, Zhuang Y, et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis. 2017;13: Sofen H, Smith S, Matheson RT, Leonardi CL, Calderon C, Brodmerkel C, 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(4): Gordon KB, Blauvelt A, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: a pooled analysis of the Phase 3 VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol. 2017;140(6): Raposo I, Torres T. Nail psoriasis as a predictor of the development of psoriatic arthritis. Actas Dermosifiliogr. 2015;106(6): Deodhar AA, Gottlieb AB, Boehncke WH, Dong B, Wang Y, Barchuk W, Xu X, Hsia EC. Efficacy and safety results of guselkumab, an anti-il23 monoclonal antibody, in patients with active psoriatic arthritis over 24 weeks: a phase 2a, randomized, double-blind, placebo-controlled study [abstract]. Arthritis Rheumatol. 2016;68(suppl 10). efficacy-and-safety-results-of-guselkumab-an-anti-il23-monoclo nal-antibody-in-patients-with-active-psoriatic-arthritis-over-24- weeks-a-phase-2a-randomized-double-blind-placebo-controlledstudy/. Accessed Jan Deepak P, Sandborn WJ. Ustekinumab and anti-interleukin-23 agents in Crohn s disease. Gastroenterol Clin N Am. 2017;46(3): Papp K, Thaçi D, Reich K, Riedl E, Langley RG, Krueger JG, 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(4): Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (resurface 1 and resurface 2): results from two randomised controlled, phase 3 trials. Lancet (London, England). 2017;6736(17): Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour J-P, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376(16): Abbvie. Risankizumab meets all co-primary and ranked secondary endpoints, achieving significantly greater efficacy versus standard biologic therapies in three pivotal phase 3 psoriasis studies ts-all-co-primary-and-ranked-secondary-endpoints-achievingsignificantly-greater-efficacy-versus-standard-biologic-therapiesin-three-pivotal-phase-3-psoriasis-studies.htm. Accessed Jan Feagan BG, Sandborn WJ, D Haens G, Panés J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389(10080): Verstockt B, Deleenheer B, Van Assche G, Vermeire S, Ferrante M. A safety assessment of biological therapies targeting the IL- 23/IL-17 axis in inflammatory bowel diseases. Expert Opin Drug Saf. 2017;16(7): Maxwell JR, Zhang Y, Brown WA, Smith CL, Byrne FR, Fiorino M, et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity. 2015;43(4): Saunte DM, Mrowietz U, Puig L, Zachariae C. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177(1): Sbidian E, Chaimani A, Garcia-Doval I, Do G, Hua C, Mazaud C, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane database Syst Rev. 2017;12(12):CD