Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammatory Conditions

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1 Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammatory Conditions Jillian Frieder 1, Dario Kivelevitch 1, Isabel Haugh 1, Ian Watson 2 and Alan Menter 1 Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-il-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn s disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here we review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-il-23 and anti-il-17 biologic agents in psoriasis and other immune-mediated diseases. A number of immune-mediated diseases, while being clinically distinct, do share similar underlying pathophysiologic processes driven by a common subset of central molecules; this offers the valuable opportunity to treat a number of these important conditions through a few specific mutual therapeutic targets. The recent discovery of the critical roles of interleukin (IL)-23 and IL-17 in the pathogenesis of psoriasis plus numerous other immune-mediated diseases has made these two cytokines key therapeutic targets for newly developed biologic agents. This review provides a brief discussion of the IL-23/IL-17 immune axis, and will present key clinical and safety data of the anti-il-23 and anti-il-17 biologic agents in the treatment of common immune-mediated inflammatory conditions. THE IL-23/IL-17 IMMUNE AXIS Through the excellent research over the last decade by immunopathologists (James Krueger and Frank Nestle), the spectrum of immune mediators (cytokines) in psoriasis and other immunemediated conditions has improved significantly. IL-23 plays a central role in T-cell-mediated responses and has been deemed a key promoter of immune-mediated conditions. Sharing a common p40 subunit with IL-12 and a unique p19 subunit, the IL- 23 heterodimer promotes signaling through both the IL-23 receptor (IL-23R) and IL-12Rb1 subunit of the IL-12 receptor (IL-12R) (Figure 1). Although related, these two cytokines maintain different biologic roles, with IL-12 and IL-23 driving T- helper (TH)-1 and TH17 cell responses, respectively. 1 With the requisite assistance of other factors such as IL-6 and transforming growth factor (TGF)-b, IL-23 induces the differentiation of na ıve CD 4 1 T cells into TH17 cells. 2 Many other innate immune cells containing the retinoic acid receptor-related orphan receptor-gt (RORgt) transcription factor are also responsive to IL-23 and are referred to as type 17 cells. 3 Collectively, TH17 and type 17 cells stimulate the production of inflammatory cytokines including IL-17, IL-22, tumor necrosis factor (TNF)-a, and granulocyte-macrophage colony-stimulating factor (GM- CSF), inciting local tissue inflammation and other immunemediated pathologic processes across the broad spectrum of immune-mediated inflammatory conditions. 4 6 The IL-17 cytokine family is comprised of six members (IL- 17A through F), each sharing varying degrees of homology and affinity for the five IL-17 receptor subsets (IL-17RA E). IL-17A and IL-17F are to date best understood and form homodimers or heterodimers, with signaling through the same receptor subunits (Figure 2). 7,8 Yet their biological functions do differ, with IL- 17A demonstrating a fold increased potency in activating inflammatory gene expression. 9 Upon receptor binding, IL-17A stimulates the upregulation of proinflammatory cytokines (i.e., IL-6, IL-8, TNF-a), chemokines (i.e., CXCL8, CXCL1, CXCL5), and metalloproteinases, which primarily culminate in granulocyte recruitment. 10 IL-17A and TNF-a act synergistically to promote increased expression of endothelial cell adhesion molecules, thereby further increasing granulocyte recruitment to sites 1 Baylor Scott and White, Division of Dermatology, Dallas, Texas, USA; 2 Texas A&M College of Medicine, Bryan, Texas, USA. Correspondence: A. Menter (amderm@gmail.com) Received 2 August 2017; accepted 25 September 2017; advance online publication 19 October doi: /cpt VOLUME 103 NUMBER 1 JANUARY

2 Administration (FDA) for use in the treatment of Crohn s disease, moderate-to-severe plaque psoriasis, and psoriatic arthritis (PsA). Numerous off-label indications for this medication have also been reported and further indications are being explored, including pediatric psoriasis. Figure 1 The IL-12 and IL-23 heterodimers are each composed of a common p40 subunit and a unique p35 and p19 subunit, respectively. Ustekinumab binds to the p40 subunit on IL-12 and IL-23, thereby inhibiting both cytokine interactions with their respective receptors. Guselkumab, tildrakizumab, risankizumab, brazikumab, and mirikizumab bind to the p19 subunit on IL-23 and inhibit its interaction with the IL-23 receptor (IL-23R). of inflammation. 11 Aberrant IL-17A production from TH17 cells, in addition to a myriad of other cellular sources, has been identified in many autoimmune diseases including psoriasis, inflammatory bowel disease (IBD) (Crohn s disease and ulcerative colitis), rheumatoid arthritis (RA), multiple sclerosis (MS), and asthma While significant gaps remain, the therapeutic efficacy of anti-il-23 and anti-il-17a biologic agents in several immune-mediated conditions confirms the fundamental role of these cytokines in multiple disease states. The anti-il-12/23 biologic agent (ustekinumab) Ustekinumab. Ustekinumab (Stelara, Janssen Biotech, Horsham, PA) is a fully human monoclonal antibody that inhibits both IL- 12 and IL-23 by binding to the p40 subunit common to these two cytokines. It is approved by the US Food and Drug Psoriasis. The safety and efficacy of ustekinumab in the treatment of moderate to severe plaque psoriasis in adults has been shown in three large multicenter, phase III, placebo-controlled clinical trials, PHOENIX 1 (NCT ), PHEONIX 2 (NCT ), and ACCEPT (NCT ) In PHEONIX 1 and PHOENIX 2, the study designs were identical through week 28, with patients randomized to ustekinumab (45 mg or 90 mg pending weight of 100 kg, respectively, weeks 0, 4, thereafter every 12 weeks) or placebo. Week 12 psoriasis area and severity index (PASI) 75 response rates for PHOENIX-1 and -2 were 67.1% and 66.7%, respectively, for ustekinumab 45 mg, and 66.4% and 75.7% for ustekinumab 90 mg, as compared to 3.1% and 3.7% for placebo. The PASI 75 responders at weeks 28 and 40 in PHOENIX 1 were rerandomized to either continue ustekinumab every 12 weeks or withdrawal of treatment until loss of response (placebo). Maintenance of PASI 75 response at week 40 was superior in patients continuing ustekinumab therapy than withdrawal (P < ); PASI 50/75/90 was generally sustained through at least week 76 in the maintenance cohort, whereas responses gradually began to decrease by week 44 in the withdrawal cohort. 19 Furthermore, 5-year data totaling 1,729 patients from both PHOE- NIX 1 and PHEONIX 2 showed maintenance of initial clinical response, with overall week 244 PASI 75 response rates of 63.4% and 76.5%, respectively, in the 45 mg group, and 72.0% and 78.6% in the 90 mg group. 20 Thus, ustekinumab demonstrated sustained responses over a long duration. Consistent clinical efficacy has also been demonstrated in Asian patients in multiple studies Figure 2 T-helper-17 (TH17) cells stimulate the release of IL-17A and IL-17F. Secukinumab and ixekizumab directly bind to IL-17A to inhibit its interaction with the IL-17 receptor (IL-17R). Brodalumab binds directly to the IL-17R, ultimately inhibiting IL-17 (A and F) ligands from binding to the receptor. CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 103 NUMBER 1 JANUARY

3 The clinical superiority of ustekinumab over etanercept was demonstrated in the ACCEPT randomized control trial (RCT). 17 This 64-week study randomized 903 patients to ustekinumab (45 mg or 90 mg) at weeks 0 and 4, or etanercept (50 mg) twice weekly for 12 weeks. Week 12 PASI 75 was achieved by 67.5% in the ustekinumab 45 mg group and 73.8% in the ustekinumab 90 mg group compared with 56.8% of those receiving etanercept. Ustekinumab demonstrated a beneficial effect in the treatment of pediatric psoriasis in a phase III study of 110 adolescent patients aged years. Week 12 PASI 75 response was achieved by 67.6% of patients receiving ustekinumab at half-standard dosing (0.375 mg/kg (60 kg), 22.5 mg (> kg), and 45 mg (>100 kg)) and 69.4% in patients receiving standard dosing (0.75 mg/kg (60 kg), 45 mg (> kg), and 90 mg (>100 kg)) vs. 5.4% for placebo (NCT ). 24 Of note, another pediatric study examining its use in children ages 6 12 years is ongoing (NCT ), with the potential for FDA approval for pediatric psoriasis over the next 6 months. Psoriatic arthritis. Two phase III clinical trials, PSUMMIT 1 (n 5 615) (NCT ) and PSUMMIT 2 (n 5 312) (NCT ), were carried out to investigate the efficacy and safety of ustekinumab in the treatment of patients with active PsA. 25,26 Patients were randomized to receive ustekinumab (45 mg or 90 mg) at weeks 0 and 4, and then every 12 weeks. Patients with less than 5% improvement at week 16 entered early-escape; patients initially on placebo were switched to 45 mg ustekinumab, and those initially on ustekinumab 45 mg were increased to 90 mg. In PSUMMIT 1, at week 24, 42.4% of the ustekinumab 45 mg group and 49.5% of ustekinumab 90 mg group achieved the primary endpoint of an American College of Rheumatology (ACR) 20 response, compared with only 22.8% of the placebo arm. Similar study arms were evaluated in PSUMMIT 2, but patients randomized to placebo crossed over to ustekinumab 45 mg at week 16. At week 24, ACR 20 was achieved by 43.8% of the combined ustekinumab-treated patients vs. 20.2% of placebotreated patients. Patients with a prior history of TNF-a biologic usage showed lower ACR 20 responses. Radiographic progression of joint damage was inhibited in the ustekinumab 45 mg and 90 mg groups. Crohn s disease. Dysregulation of the adaptive immune response in Crohn s disease is significantly influenced by the activities of both IL-12 and IL-23. Activation of T-cell proliferation is stimulated by IL-12, whereas IL-23 has a major influence over the expansion of TH17 cells. The blockade of these two cytokines with ustekinumab has shown significant clinical improvement in Crohn s disease patients. To date, three phase III clinical trials have been carried out to evaluate the efficacy and safety of ustekinumab for the treatment of moderately to severely active Crohn s disease, with FDA approval for this indication obtained in September of Two of these trials, UNITI-1 (n 5 741) (NCT ) and UNITI-2 (n 5 628) (NCT ), were induction trials that included patients who had an inadequate response to TNF-a antagonists or other conventional therapies (i.e., corticosteroids and immunomodulators), or unacceptable side effects. In both trials, patients were randomized into one of three groups: one with an initial intravenous (i.v.) dose of ustekinumab at 130 mg, ustekinumab at 6 mg per kg of body weight, or placebo. The primary endpoint for the induction trials was a clinical response at week 6 defined as a decrease from baseline in the Crohn s Disease Activity Index (CDAI) score of 100 points or a CDAI score <150. In UNITI-1, clinical response was achieved by 34.3%, 33.7%, and 21.5%, and in UNITI-2 in 51.7%, 55.5%, and 28.7%, in each of the dosing groups, respectively. Patients who completed these induction trials with a response to ustekinumab (n 5 397) were continued in the maintenance trial, IM-UNITI (NCT ). Patients were again randomized to receive subcutaneous (s.c.) maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. In these groups, respectively, 53.1%, 48.8%, and 35.9% obtained remission at week 44. Other immune-mediated inflammatory conditions. The use of ustekinumab for a variety of other immune-mediated conditions has been evaluated with variable success. It did not show a benefit over placebo for the treatment of multiple sclerosis (NCT ) or pulmonary sarcoidosis and/or skin sarcoidosis (NCT ), suggesting a non-key role of the TH1/ TH17 pathways in these diseases. 28,29 A small (n 5 33) proof-ofconcept study for atopic dermatitis (NCT ) supported the benefit of ustekinumab, with patients on active treatment achieving higher, but not statistically significant, rates of SCORAD 50 (scoring atopic dermatitis) or greater responses compared to placebo (week 16 odds ratio: 1.93, 95% confidence interval (CI) ). Ustekinumab was also associated with significant histologic responses defined as a decrease in epidermal thickness and k16 protein staining, as well as beneficial effects on inflammatory gene modulation. 30 Other clinical trials have been completed to assess ustekinumab s efficacy in spondyloarthritis (NCT ), hidradenitis suppurativa (NCT ), type 1 diabetes mellitus (NCT ), palmoplantar psoriasis (NCT ), and primary biliary cirrhosis (NCT ). There are also ongoing clinical studies exploring the possibility of its use in systemic lupus erythematosus (NCT ), giant cell arteritis (NCT ), gastrointestinal inflammation associated with common variable immunodeficiency (NCT ), uveitis (NCT ), ulcerative colitis (NCT ), scalp psoriasis (NCT ), as well as a planned study for Bechet s disease (NCT ). Safety. Ustekinumab usage has been reported in clinical trials to be associated with increased rates of adverse events (AEs) including upper respiratory infections (URIs), arthralgia, headache, pyrexia, nausea, nasopharyngitis, abdominal pain, injection site reaction, and fatigue. Relating to serious adverse events (SAEs), rare cases of serious infections and cardiovascular events were reported. Safety data from patients with psoriasis receiving ustekinumab in the PHOENIX 1 and PHEONIX 2 trials showed two deaths, 11 serious infections, and five cardiovascular events. Deaths due to alcohol intoxication and aspiration in a patient in 90 VOLUME 103 NUMBER 1 JANUARY

4 the placebo to ustekinumab 45 mg crossover group, as well as nonischemic sudden cardiac death in a patient with an underlying dilated cardiomyopathy plus other comorbidities, have been reported. 17,18,31 Three deaths were reported in the ACCEPT study: etanercept group (motor vehicle accident), ustekinumab 45 mg group (gunshot wound), and ustekinumab 90 mg group (multisystem organ failure and sepsis in a patient with human immunodeficiency virus). Three major adverse cardiovascular events (MACEs) were reported in the ACCEPT study, all in ustekinumab-exposed patients. In the initial stages of ustekinumab studies in psoriasis, multiple MACE events were noted. 32 Yet registry data (PSOLAR) after 7 years has shown neither an increase nor decrease in MACE events with ustekinumab. In the PsA trials, PSUMMIT-1 and -2, there were no deaths, seven serious infections, and five cardiovascular events in ustekinumabexposed patients. 25,26 Lastly, in the Crohn s trials, UNITI-1, UNITI-2, and IM-UNITI, no deaths or major adverse cardiac events were reported, with serious infections being reported in 12 ustekinumab-exposed patients. 27 Despite the initial concern of MACE events in clinical trials with ustekinumab, the subsequent 7 years of usage in clinical practice has not confirmed this important issue. 32 The continued use of ustekinumab for patients with moderate to severe psoriasis has been shown to be higher than with the TNF-a agents approved for psoriasis, with fewer ustekinumab patients dropping out of therapy. This is likely due to the early 12-week dosage adjustment as well as the lack of significant antibodies being reported with ustekinumab vs. the TNF-a agents. Anti-IL-17 agents Brodalumab. Brodalumab (Siliq, USA, Valeant Pharmaceuticals, Laval, Canada and Europe, Leo Pharma, Copenhagen, Denmark) is a human IgG2 monoclonal antibody that binds to the subunit A of the IL-17 receptor (IL-17RA) and inhibits the downstream activities of IL-17A, IL-17C, IL-17E, IL-17F, and IL-17A/F heterodimer ligands. 33 Brodalumab was approved by the FDA in February 2017 for the treatment of adult patients with moderate to severe plaque psoriasis at a recommended dosage of 210 mg s.c. at weeks 0, 1, and 2 followed by 210 mg every 2 weeks. 34 Psoriasis. Three phase III trials have evaluated the efficacy of brodalumab in plaque psoriasis: AMAGINE-1 (NCT ), -2 (NCT ), and -3 (NCT ). 35 AMAGINE-1 was a randomized, double-blind, placebo-controlled study in which 661 patients with moderate to severe psoriasis underwent a 12-week induction phase followed by a withdrawal/treatment phase through week During the induction phase, patients received brodalumab 210 mg (n 5 222), 140 mg (n 5 219), or placebo (n 5 220) once every 2 weeks. Both PASI 75 and static physician global assessment (spga) 0/1 scores were achieved by a significantly greater percentage of both brodalumab groups compared to placebo. Week 12 PASI 75 response rates were 83.3%, 60.3%, and 2.7%, respectively. PASI 90/100 responses were 70.3%/41.9% and 42%/23.3% for patients in the 210 mg and 140 mg brodalumab groups, respectively, compared to 0.9%/0.5% in the placebo group. Of significant importance, clinical responses were sustained up to week 52. A significant majority of patients who lost disease control following brodalumab withdrawal recovered efficacy within 12 weeks of restarting treatment. 35 AMAGINE-2 and -3 were two large double-blind, placebocontrolled trials with identical designs that evaluated the safety and efficacy of 210 mg and 140 mg doses of brodalumab every 2 weeks compared to ustekinumab (45 mg doses for patients 100 kg and 90 mg for patients >100 kg with two initial dosages 1 month apart) and placebo in patients with moderate to severe plaque psoriasis. 35,37 At week 12, patients receiving brodalumab were randomly reassigned to one of four maintenance regimens: 210 mg every 2 weeks, 140 mg every 2 weeks, 140 mg every 4 weeks, or 140 mg every 8 weeks; patients initially assigned to ustekinumab continued receiving ustekinumab every 12 weeks, and patients receiving placebo were switched to brodalumab 210 mg once every 2 weeks. In both studies, brodalumab 210 mg revealed superiority over ustekinumab, with higher PASI 100 response rates at 12 weeks. In the patients who received brodalumab therapy subsequent to their ustekinumab treatment, a significant number achieved PASI 75 scores, with over 40% achieving PASI 100. Similarly, most patients who received brodalumab after placebo achieved PASI 75 responses, with the majority achieving PASI 100 by week 52. A dose of 210 mg delivered every 2 weeks showed superior results for maintenance of clinical response. 35 Psoriatic arthritis. An RCT assessed the efficacy and safety of brodalumab in 168 PsA patients (brodalumab 140 mg (n 5 57), brodalumab 280 mg (n 5 56), and placebo (n 5 55)). At week 12, the brodalumab 140 mg and 280 mg groups showed higher rates of ACR 20 and ACR 50 responses than the placebo group (ACR 20: 37% (P ) and 39% (P ), respectively, vs. 18%; ACR 50: 14% (P ) and 14% (P ), respectively, vs. 4%). Further rate improvements in the severity scores were seen at week 24, with ACR 20 rates reaching 51% and 64% for brodalumab 140 mg and 280 mg, respectively; responses were sustained through week Consistent results for brodalumab were seen in a Japanese study. 39 Other immune-mediated inflammatory conditions. The assessment of brodalumab for use in other immune-mediated conditions is limited. Brodalumab demonstrated a lack of therapeutic efficacy for the treatment of moderate to severe Crohn s disease. In fact, this phase II study was terminated early due to a disproportionate number of patients experiencing worsening of disease (NCT ). 40 Due to these findings, patients with a known history of Crohn s disease were excluded from subsequent phase II and III brodalumab psoriasis clinical trials. Brodalumab (140, 210, or 280 mg) was also evaluated for use in severe asthma in a phase II RCT (NCT ) and exhibited no significant changes in the Asthma Control Questionnaire (ACQ) score and forced-expiratory volume-one second (FEV1) from baseline to week 12, compared to placebo. 41 A phase III study to evaluate the efficacy of brodalumab in ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis patients compared to CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 103 NUMBER 1 JANUARY

5 placebo is ongoing (NCT ). The endpoint is the proportion of subjects achieving an Assessment of Spondyloarthritis International Society (ASAS) 40 response at week 16. No data have been published to date. Safety. In AMAGINE-1, brodalumab (210 mg and 140 mg) was associated with more AEs (59% and 57.5%, respectively) and SAEs (1.8% and 2.7%) than placebo (AEs: 50.9%; SAEs: 1.4%), with the majority being of mild or moderate severity. The most frequently reported AEs (occurring in 5% of patients in any treatment group) were nasopharyngitis, URI, and headache. By week 12, one case of oral candidiasis and neutropenia occurred in the brodalumab 140 mg cohort. Equal rates of depression (0.5%) occurred in both brodalumab groups and placebo. 36 During the induction phase of the AMAGINE-2 and -3 trials, rates of AEs were higher for brodalumab and ustekinumab than placebo, with the most common being nasopharyngitis, URI, headache, and arthralgia. Transient, reversible neutropenia occurred more frequently in brodalumab and ustekinumab groups compared to placebo. During the first 12 weeks, more candida infections were reported for patients receiving brodalumab than those on ustekinumab or placebo (1.2% in all brodalumab groups vs. 0.5% for both ustekinumab and placebo), highlighting the role of IL-17 in antifungal immunity. 42 One patient in the AMAGINE-2 maintenance phase experienced new-onset Crohn s disease and was subsequently withdrawn from the study. Based on increased rates of IBD in clinical trials, brodalumab is contraindicated in patients with Crohn s disease. 43 Three deaths occurred after completion of these studies as a result of: suicide (27 days after the last dose), hemophagocytic histiocytosis syndrome, and cardiomyopathy. Another suicide was reported in one patient while enrolled in the open-label extension of AMAGINE-2 (19 days after receiving the last dose of brodalumab 210 mg every 2 weeks). In total, there were six suicides reported for all of the brodalumab clinical trials: four in psoriasis trials, one in RA, and one in PsA. Importantly, no studies have found a causal association between the use of brodalumab and suicidal ideation or completed suicide. Nevertheless, brodalumab has been approved by the FDA with a black box warning based on the suicide issue. 44,45 Thus, the SILIQ Risk Evaluation and Mitigation Strategies (REMS) program was implemented in the US with the intent of mitigating the risk of suicidal ideation and behavior associated with brodalumab. This program promotes the education of prescribers and patients regarding these mental health risks and ensures medical attention is sought in the case of suicidal thoughts and behavior, new or worsening depression, anxiety, or other mood changes. Both prescribing physicians and patients are required to enroll in the REMS program prior to initiating treatment. Additionally, pharmacies must be certified and only dispense brodalumab to authorized patients. 46 A REMS program has not been initiated in Europe. Ixekizumab Ixekizumab (Taltz, Eli Lilly, Indianapolis, IN) is a humanized IgG4 monoclonal antibody that selectively binds and neutralizes the activity of IL-17A. In 2016, it was approved in the US and Europe for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy. To date, it is not yet approved for PsA, although approval is expected shortly. Ixekizumab is administered s.c. via autoinjector or prefilled syringe at a recommended dose of 160 mg at baseline followed by 80 mg every 2 weeks through week 12, and thereafter monthly. 47 Psoriasis. The safety and efficacy of ixekizumab was assessed in three pivotal phase III, randomized, double-blind, placebocontrolled trials for moderate to severe plaque psoriasis. 48 In the UNCOVER-1 trial (NCT ), patients were assigned to placebo, ixekizumab 80 mg every 2 weeks (IXEQ2W), or ixekizumab 80 mg monthly (IXEQ4W). PASI 75 response rates for IXEQ2W, IXEQ4W, and placebo were 89.1%, 82.6% and 3.9%, respectively. Additionally, both ixekizumab dose groups achieved excellent PASI 90/100 response rates (IXEQ4W: 64.6%/33.6%; IXEQ2W: 70.9%/35.3%). 48 The UNCOVER-2 and -3 trials (NCT , NCT ) included an additional etanercept 50 mg comparator arm. At week 12, IXEQ4W and IXEQ2W were superior to etanercept and placebo with regard to PASI 75 and spga 0/1 scores (P < for all comparisons). Ixekizumab demonstrated rapid clinical responses, with a greater proportion of patients attaining PASI 75 by week 1 compared to etanercept (UNCOVER-2: IXEQ4W vs. etanercept; P ; IXEQ2W vs. etanercept; P ). Additionally, a greater proportion of patients treated with either ixekizumab dose achieved PASI 90/100 compared to etanercept at week 12. Clinical responses were sustained through week 60 in the extension period of UNCOVER-3, where all patients were either maintained, or switched, to monthly ixekizumab (PASI 75/90/100 response rates: IXEQ2W (weeks 0 12) followed by monthly (weeks 12 60): 83%/73%/55%; IXEQ4W (weeks 0 60): 80%/71%/52%). 48,49 Patients from UNCOVER-1 and UNCOVER-2 who attained an spga score of 0/1 at week 12 were randomized to 80 mg IXEQ4W, IXEQ12W, or placebo. By week 60, 73.8% of patients on IXEQ4W dosing maintained an spga of 0/1 compared to 39.0% on IXEQ12W dosing and 7.0% on placebo. Higher PASI 90/100 rates were also maintained through week 60 for monthly ixekizumab dosing, whereas they were reduced with Q12W dosing. 48 Psoriatic arthritis. The safety and efficacy of ixekizumab in the treatment of active PsA in biologic-na ıve patients was evaluated in the phase III SPIRIT-P1 trial (NCT ). 50 Patients were assigned to 80 mg IXEQ4W, IXEQ2W, adalimumab 40 mg every 2 weeks, or placebo. Compared to placebo, both ixekizumab dose groups achieved significantly higher ACR 20 response rates at weeks 12 and 24 (IXEQ2W: 60.2%/62.1%; IXEQ4W: 57.0%/57.9% vs. placebo: 31.3%/30.2%; P for all comparisons). Week 24 ACR 20 rates for adalimumab were also superior to placebo (57.4% vs. 30.2%; P 0.001). Progression of structural damage as measured by the modified total Sharp score (mtss) was significantly less for IXEQ4W (0.17), 92 VOLUME 103 NUMBER 1 JANUARY

6 IXEQ2W (0.08), and adalimumab (0.10) compared to placebo (0.49) (P 0.01 for all comparisons). Additionally, both ixekizumab and adalimumab were associated with greater improvements in disease activity and physical function compared to placebo as assessed by the Disease Activity Score in 28 joints using C- reactive protein levels (DAS28-CRP) and Health Assessment Questionnaire Disability Index (HAQ-DI). 50 Rheumatoid arthritis. Ixekizumab demonstrated efficacy for the treatment of RA in a phase II RCT. 51 Patients were randomized to placebo or various doses of ixekizumab based on previous biologic exposure (3 mg, 10 mg, 30 mg, 80 mg, or 180 mg) and inadequate anti-tnf treatment response (80 mg or 180 mg). In the biologic-na ıve cohort, a greater proportion of patients on ixekizumab attained ACR 20 responses at multiple assessed timepoints compared to placebo; a significant dose response relationship was observed (P ). Furthermore, ACR 50 and 70 responses were achieved by the majority of ixekizumab doses. ACR 20 response rates at week 12 were significantly higher for both ixekizumab doses in RA patients with an inadequate response to TNF-a inhibitors, compared to placebo (P < 0.05 for each comparison). Statistically significant differences in ACR 50 rates were observed between ixekizumab 80 mg and placebo, whereas ACR 70 response rates were similar across the board. 51 ACR 20/50/70 responses at week 16 were maintained, or improved, by week 64 in the open-label extension where patients continued 160 mg of ixekizumab at weeks 16, 18, and 20, followed by monthly dosing. 52 Other immune-mediated inflammatory diseases. Ixekizumab clinical trials for bullous pemphigoid (phase II, NCT ), pyoderma gangrenosum (phase II, NCT ), and axial spondyloarthritis (phase III NCT ) are currently in the planning stages. Safety. In the pooled safety data from the three pivotal trials for plaque psoriasis, the most common AEs included nasopharyngitis, URI, injection-site reaction/erythema, and headache. 48 Similar exposure-adjusted incidence rates of at least one SAE occurred in ixekizumab and placebo cohorts, with cellulitis the most frequent for ixekizumab (three cases). Candidiasis, especially oral, occurred significantly more often in the IXEQ2W group than placebo, and more frequently in IXEQ2W than IXEQ4W. Neutropenia, mostly mild (grades 1 and 2), was also more common in ixekizumab than placebo; more severe grades 3 and 4 neutropenia occurred in eight and two patients, respectively, exposed to ixekizumab through the 60-week treatment period. During the induction period, there were comparable rates of MACEs between IXEQ4W and placebo; no MACEs occurred in the IXEQ2W cohort during the first 12 weeks. Of all patients treated with ixekizumab, there were seven cases of ulcerative colitis and four cases of Crohn s disease, with an incidence rate of 1 in 1,000 for Crohn s disease and 2 in 1,000 for ulcerative colitis. 48 Another study evaluating seven randomized controlled and uncontrolled trials for ixekizumab (n ) reported 19 adjudicated cases of IBD (Crohn s disease: 7; ulcerative colitis: 12), concluding these occurrences to be uncommon (<1%). 53 The package insert includes a warning for patients with a history of IBD to be monitored closely while on ixekizumab. 47 Secukinumab Secukinumab (Cosentyx, Novartis Pharma, Basel, Switzerland) is a recombinant human monoclonal IgG1/kappa antibody that selectively targets IL-17A and inhibits its binding to the IL-17 receptor. It is approved in the US and Europe for the treatment of moderate to severe plaque psoriasis, PsA, and AS. Ongoing clinical evaluation for its use in a variety of other immunemediated inflammatory conditions demonstrates the broad therapeutic potential of this biologic agent. 54,55 Psoriasis. The efficacy of secukinumab for the treatment of moderate to severe plaque psoriasis has been well documented in numerous phase II and III RCTs In the pivotal phase III ERASURE study (NCT ), PASI 75 at week 12 was obtained by a greater proportion of patients on secukinumab 300 mg and 150 mg compared to placebo (81.6% and 71.6%, respectively, vs. 4.5%; P < for both comparisons). 62 Significantly higher PASI 90/100 response rates plus greater patientreported improvements in itch, pain, scaling, and health-related quality of life (HRQoL) measures were observed for both secukinumab doses (P < for all comparisons), with superior clinical improvements for all endpoints maintained through 52 weeks. 62 Secukinumab demonstrated superiority to etanercept in the phase III FIXTURE study (NCT ), with week 12 PASI 75 responses of 77.1%, 67.0%, and 44.0% for secukinumab 300 mg, 150 mg, and etanercept 50 mg, respectively (P < for each dose comparison). 62 PASI 50 responses were achieved more rapidly with each secukinumab dose than etanercept (median time: 3.0 weeks (300 mg) and 3.9 weeks (150 mg) vs. 7.0 weeks; P < for both comparisons). Secukinumab superiority was observed in other key endpoints, with clinical improvements sustained through week In the CLEAR trial (NCT ) head-to-head comparison, secukinumab achieved superior clinical responses to ustekinumab with regard to PASI 90 response at week 16 (79.0% vs. 57.6%; P <0.001), PASI 90 at week 52 (76.2% vs. 60.6%; P < ), and PASI 100 at week 52 (45.9% vs. 35.8%; P ). 63 Secukinumab showed greater improvements in patient-reported itch (77.6% vs. 68.3%), pain (80.1% vs. 58.8%), scaling (82.6% vs. 71.8%), and Dermatology Life Quality Index (DLQI) scores. 63 Secukinumab was also efficacious in treating generalized pustular psoriasis (GPP) in one open-label phase III Japanese study (NCT ), with 83.3% of subjects achieving treatment success as defined by Clinical Global Impression (CGI) scores of very much improved (n 5 9/12) and much improved (n 5 1). 64 In the phase IIIb GESTURE clinical trial (NCT ), secukinumab was superior to placebo in treating hyperkeratotic palmoplantar psoriasis (hppp), a traditionally difficult-to-treat form of psoriasis 65 ; 33.3%, 22.1%, and 1.5% of patients on CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 103 NUMBER 1 JANUARY

7 secukinumab 300 mg, 150 mg, and placebo, respectively, achieved palmoplantar investigator global assessment (IGA) scores of 0/1 at week 16 (P < for 300 mg vs. placebo; P for 75 mg). Greater reductions in palmoplantar PASI scores were consistently seen at all assessed timepoints for both secukinumab dose groups compared to placebo (week 16: 300 mg: 54.5%; 150 mg: 35.3%; placebo: 4.0; P < and P , respectively). 65 Psoriatic arthritis. The efficacy of secukinumab for the treatment of PsA was assessed in the FUTURE 2 phase III clinical trial (NCT ), which randomized 397 patients to secukinumab 300 mg, 150 mg, 75 mg, or placebo. 66 At week 24, ACR 20 response rates were significantly higher for each secukinumab dose group compared to placebo (300 mg: 54% vs. placebo: 15.0% (P < ); 150 mg: 51.0% (P < ); 75 mg: 29% (P )). Secukinumab 300 mg and 150 mg doses reached significantly greater week 24 PASI 75/90 response rates compared to placebo, and maintained clinical responses through week Secukinumab exhibited significant improvements in patientreported outcomes (PROs) in terms of PsA in the FUTURE 1 phase III trial (NCT ). 67 Compared to placebo, i.v. secukinumab 10 mg/kg followed by s.c. secukinumab 150 mg or 75 mg achieved significantly greater improvements in baseline patient global assessment of disease activity (PtGA) and patient assessment of PsA pain by visual analog scale (VAS) at all assessed timepoints through week 24 (P < for all comparisons). Significant improvements pertaining to work productivity, activities of daily living, social and emotional well-being, physical function, and pain were also achieved by secukinumab and sustained through week Prolonged clinical responses were noted at week 104, with ACR 20 rates of 66.8% and 58.6% for secukinumab 150 mg and 75 mg, respectively. 68 No radiographic disease progression was identified following 2 years of treatment in the majority of patients in both the 150 mg and 75 mg dose groups (84.3% and 83.8%). 68 Ankylosing spondylitis. In two phase III randomized, double-blind studies, secukinumab was efficacious and superior to placebo in treating AS inadequately controlled with nonsteroidal antiinflammatory drugs (NSAIDs) and anti-tnf-a agents. 69 In the MEA- SURE 1 trial (NCT ), patients were randomized to placebo or i.v. secukinumab 10 mg/kg (weeks 0, 2, and 4) followed by s.c. secukinumab 150 mg or 75 mg monthly. In MEASURE 2 (NCT ), patients received secukinumab 150 mg, 75 mg, or placebo (weeks 1, 2, 3, and 4, then monthly). The primary outcome of ASAS 20 response rates at week 16 for both studies were 61% for secukinumab 150 mg, 41 60% for secukinumab 75 mg, and 28 29% for placebo (all significant except for P for 75 mg vs. placebo in MEASURE 2). The secondary endpoint of ASAS 40 responses were also significantly higher for secukinumab 150 mg (36 42%) compared to placebo (11 13%) in each study; secukinumab 75 mg ASAS 40 responses were insignificantly higher compared to placebo in MEASURE 2 (26% vs. 11%; P ). Clinical response rates achieved at week 16 were maintained through week 52 in both studies. Ultimately, secukinumab 150 mg was shown to be more efficacious than the 75 mg dose in treating AS. 69 Rheumatoid arthritis. In a phase III study (NCT ), 551 patients with active RA with an inadequate response or intolerance to anti-tnf-a agents were randomized to i.v. secukinumab 10 mg/kg (weeks 0, 2, and 4) followed by s.c. secukinumab 150 mg or 75 mg monthly, abatacept, or placebo. 70 ACR 20 response rates at week 24 were significantly higher for secukinumab 150 mg compared to placebo (30.7% vs. 18.1%; P ), but not secukinumab 75 mg (28.3%; P ). Notably, abatacept obtained numerically higher ACR 20 response rates than secukinumab (42.8% vs. 30.7%). Additionally, more patients on secukinumab 150 mg achieved reductions in the DAS28-CRP compared to placebo (P ); no significant difference was observed with secukinumab 75 mg. Only abatacept achieved significant ACR 50 responses (P < 0.05) and resulted in significant reductions in the HAQ-DI (P < 0.05) compared to placebo at week This study suggests that higher doses of secukinumab may be efficacious in treating RA, with further clinical studies required to confirm these results. Other immune-mediated inflammatory conditions. Like brodalumab, secukinumab demonstrated a lack of efficacy for use in Crohn s disease in a small proof-of-concept (n 5 59) clinical trial (NCT ). 71 Reductions in the CDAI were greater for placebo ( 63.1) than secukinumab ( 29.2) at week 6, and there was an observed trend of increased disease activity in patients receiving secukinumab. 71 In a phase III RCT for recurrent uveitis in Behcet s disease (NCT ), there was no significant difference between secukinumab and placebo in reducing the rate of ocular exacerbations of posterior uveitis or panuveitis. 72 However, patients on monthly secukinumab had a significant reduction in immunosuppressive medication use from baseline to week 24, compared to placebo (P ). 72 Secukinumab is currently undergoing clinical evaluation for use in hidradenitis suppurativa (phase I; NCT ), pyoderma gangrenosum (phases I and II; NCT ), and atopic dermatitis (phase II; NCT ). Studies in alopecia areata (NCT ), asthma (NCT ), type 1 diabetes mellitus (NCT ), polymyalgia rheumatica (NCT ), and relapsing multiple sclerosis (NCT ) have been terminated for various reasons, although future trials for one or more of these conditions may yet be reinitiated. Safety. Nasopharyngitis, diarrhea, and URI are among the most frequently reported AEs for secukinumab. In placebo-controlled trials, overall infection rates were higher for secukinumab (28.7%) than placebo (18.9%); higher rates of serious infections occurred in subjects treated with placebo (placebo: 0.3%; secukinumab: 0.14%). 54 Secukinumab and etanercept showed comparable safety profiles in the FIXTURE trial, but notable differences in numerically higher rates of candidiasis for secukinumab (4.7% (300 mg); 2.3% (150 mg); 1.2% (etanercept)), and numerically higher injection-site reactions for etanercept (secukinumab: 94 VOLUME 103 NUMBER 1 JANUARY

8 Table 1 Comparison of rates of candidiasis between biologic agents Drug name Candidiasis incidence rates Ustekinumab 63, 92a 4.35% (n 5 23/1068) Brodalumab 36, 92b 4.4% (n 5 169/3828) Ixekizumab 48c 3.5% (n 5 128/3736) Secukinumab 73d 2.0% (n 5 69/3430) 80, 81, 84e Guselkumab Insufficient data 85, 86f Risankizumab Insufficient data Tildrakizumab 89g Insufficient data a Data from the AMAGINE-2, -3, and CLEAR trials through 52 weeks in all patients exposed to ustekinumab. b Data from the AMAGINE-1, -2, and -3 clinical trials through 52 weeks in all patients exposed to brodalumab. c Data through 60 weeks during the combined treatment period in all patients with exposure to ixekizumab during the UNCOVER-1, -2, and -3 clinical trials. d Data from a pooled data analysis of 10 phase II and III clinical trials for moderate-to-severe plaque psoriasis through 52 weeks of all secukinumab doses and placebo-to-secukinumab crossover patients. e No specific data on rates of candida infections were reported in clinical trials. f No specific data on rates of candida infections were reported in clinical trials. g No specific data on rates of candida infections were reported in clinical trials, but candida infections were infrequent in both resurface -1 and -2 clinical trials. 0.7%; etanercept: 11.0%). Neutropenia occurred at very low rates for both agents, with most cases being of mild severity and few of moderate-to-severe (Grade 3: 1.0% for secukinumab and 0% for etanercept; Grade 4: 0.3% for etanercept and 0% for secukinumab). 62 Secukinumab and ustekinumab also showed similar safety profiles in the CLEAR trial with no unexpected AEs observed. 63 In another large pooled safety analysis including 10 phase II and III clinical trials, incidence rates for Crohn s disease and ulcerative colitis through 52 weeks of secukinumab exposure were 0.11 and 0.15, respectively. 73 The package insert recommends caution when prescribing secukinumab to patients with a history of IBD. Similar safety data were observed in PsA and AS clinical trials. Full prescribing information can be found in the package insert. 54 SPECIAL SAFETY CONSIDERATIONS FOR ANTI-IL-17 AGENTS IL-17 maintains a fundamental role in host defense against a variety of infections (i.e., bacterial, fungal, viral, and parasitic) through the stimulation of proinflammatory cytokines, chemokines, and neutrophil recruitment. Additionally, single-nucleotide polymorphisms in IL-17 and IL-17RA slightly enhance the risk of fungal diseases such as candidiasis and bacterial infections like mycobacterium tuberculosis. 74,75 As mentioned previously, increased rates of infections, particularly candidiasis, as well as neutropenia have been reported in clinical trials of anti-il-17 biologics (Table 1). A large meta-analysis of anti-il-17 biologic clinical trials for psoriasis and PsA found candida infection rates of 4.0%, 1.7%, and 3.3% for brodalumab, secukinumab, and ixekizumab, respectively, compared to 0.3%, 2.3%, and 0.8% for placebo, ustekinumab, and etanercept. 76 While the majority of cases were in the oral cavity, and of mild to moderate severity, this increased risk warrants close monitoring of patients during treatment with these IL-17 agents. With regard to IBD, studies have demonstrated elevated levels of TH17 cells and IL-17 in patients with Crohn s disease, indicating a role of the IL-17 cytokine in disease pathogenesis. 12,77 However, other animal studies suggested a protective role of IL- 17 through supporting the migration of a subset of antiinflammatory regulatory TH17 cells to the gut mucosa. 78 The latter was supported by results from both brodalumab and secukinumab clinical trials for Crohn s disease, which reported high rates of disease exacerbation (Table 2). 40,71 Overall, data associates IL-17 inhibition with a low risk (<1%) of IBD, but caution must be exercised in treating patients with a history of Crohn s disease or ulcerative colitis. 53 One of the major benefits of the three IL-17 agents discussed above are the large number of patients, i.e., 5,000, entered into clinical trials. This is substantially larger (2 33) than all three TNF-a agents and anti-il-12/23 biologic clinical trials in psoriasis. In addition, the significant improvement in outcome measures over our current TNF-a agents is of major benefit to patients with moderate to severe psoriasis. As there is a 3-fold increase in Crohn s disease in the psoriasis population, caution needs to be exercised in both the treatment with IL-17 agents in Table 2 Comparison of rates of IBD between biologic agents IBD incidence rates Drug name (Crohn s disease and ulcerative colitis) Ustekinumab 92a 0.00% (n 5 0/613) Brodalumab 36, 92b 0.03% (n 5 1/3828) Ixekizumab 48c 0.3% (n 5 11/3736) Secukinumab 73d 0.20% (n 5 7/3430) Guselkumab 80e 0.00% (n 5 0/503) Risankizumab 85, 86f 0.00% (n 5 0/157) Tildrakizumab 89g 0.00% (n 5 0/2862) IBD, inflammatory bowel disease. a Data from the AMAGINE-2 and -3 clinical trials through 52 weeks. b Cases of CD (1) through 52 weeks in all patients exposed to brodalumab in the AMAGINE-1, -2, and -3 clinical trials. c Cases of CD (4) and UC (7) through 60 weeks during the combined treatment period in all patients with exposure to ixekizumab during the three UNCOVER trials. Of note, three patients on placebo reported CD (days 23, 70, and 134). d Cases of Crohn s disease (CD) (3) and ulcerative colitis (UC) (4) through 52 weeks from a pooled data analysis of 10 phase II and III clinical trials for moderateto-severe plaque psoriasis. Includes all doses of secukinumab and placebo-tosecukinumab crossover patients. Two of three cases of Crohn s disease had a history of Crohn s disease and two of the four cases of ulcerative colitis had a history of ulcerative colitis. e Data from the VOYAGE-1 trial through week 48 of all patients exposed to guselkumab. f Data from the proof-of-concept study and phase II study. g Data from the resurface-1 and -2 trials in the all-participants-as-treated population who received at least one dose of tildrakizumab in part 1 or part 2 of the study. resurface 1 safety data is through week 64 and resurface 2 safety data is through week 28. CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 103 NUMBER 1 JANUARY

9 patients with IBD, as well as an explanation to patients of the associated risks (1:1,000 for Crohn s disease and 2:1,000 for ulcerative colitis) with this class of biologic agents. Anti-IL-23 agents Guselkumab. Guselkumab (CNTO 1959, Janssen Biotech) is a fully humanized IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL-23 to inhibit its downstream signaling. 79 It currently is approved for the treatment of adults with moderate to severe plaque psoriasis. Clinical evaluation is also being performed for palmoplantar pustulosis (phase III, NCT ), pustular psoriasis (phase III, NCT ), PsA (phase III, NCT , NCT ), and RA (phase II, NCT ). Psoriasis. Guselkumab demonstrated efficacy in three pivotal phase III RCTs. In VOYAGE-1 (NCT ), patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks (Q8W)), placebo (weeks 0, 4, and 12) followed by guselkumab (weeks 16 and 20, then Q8W), or adalimumab (80 mg; baseline; 40 mg: week 1, then Q2W). 80 At week 16, guselkumab was superior to placebo (P < 0.001) in terms of IGA score of 0/ 1 (85.1% vs. 6.9%) and PASI 90 (73.3% vs. 2.9%). Additionally, guselkumab achieved significantly greater rates of IGA 0/1 and PASI 90 compared to adalimumab (P < 0.001) at week 16 (IGA: 85.1% vs. 65.9%; PASI 90: 73.3% vs. 49.7%) through week 48 (IGA 0/1: 80.5% vs. 55.4%; PASI 90: 76.3% vs. 47.9%). PASI 100 responses were significantly greater for guselkumab than adalimumab at weeks 24 and 48 (P < 0.001). In the placebo crossover group, similar clinical responses were observed after guselkumab initiation at week The same comparator arms were included in VOYAGE-2 (NCT ), with the exception of PASI 90 responders rerandomized at week 28 to guselkumab, or placebo with guselkumab reinitiation after loss of response; nonresponders at week 28 continued guselkumab. 81 From weeks 28 48, the guselkumab continuation cohort demonstrated greater maintenance of clinical response compared to the withdrawal groups (P < 0.001), with week 48 PASI 90 rates of 88.6% vs. 36.8%, respectively. The median time to loss of PASI 90 response after withdrawal was 15.2 weeks (23 weeks post the last guselkumab dose). In adalimumab patient nonresponders who switched to guselkumab at week 28, PASI 90 and 100 response rates reached 66.1% and 28.6%, respectively, at week The NAVIGATE phase III trial (NCT ) evaluated the efficacy of guselkumab in patients who had an inadequate response (IGA 2) to ustekinumab (45 mg or 90 mg at weeks 0 and 4) by week 16. In all, 268 patients were randomized to guselkumab 100 mg (weeks 16 and 20, then Q8W through week 44), or to continue ustekinumab Q12W (through week 40). Patients who switched to guselkumab had consistently greater clinical improvements between weeks 28 40, with a greater proportion of patients having twice as many office visits with 2-point improvement in IGA from week 16, and an IGA score of 0/1 (1.5 and 0.7, respectively; P < 0.001). Compared to ustekinumab, guselkumab achieved higher rates of IGA 0/1 scores and PASI 90 responses at week 52 (P < 0.001). 82 Psoriatic arthritis. In a phase IIa RCT (NCT ), 149 patients with active PsA and 3% body surface area (BSA) of plaque psoriasis were randomized (2:1) to guselkumab 100 mg or placebo. 83 At week 16, patients with <5% improvement in joint activity were switched to open-label ustekinumab; at week 24, patients on placebo crossed over to guselkumab. ACR 20 response rates at week 24 were significantly greater with guselkumab than placebo (58.0% vs. 18.4%; P < 0.001). Guselkumab also achieved significantly greater ACR 50/70 and PASI 75/90/ 100 responses at week 24. Additionally, patients treated with guselkumab reported significantly greater improvements in physical function, enthesitis, dactylitis, joint symptoms, and overall quality of life. Further evaluation for PsA will be performed in upcoming phase III trials (NCT , NCT ). Rheumatoid arthritis. Guselkumab was evaluated for use in RA in a phase II study (NCT ), which randomized patients to placebo, ustekinumab 90 mg Q8W, ustekinumab 90 mg Q12W, guselkumab 50 mg Q8W, and guselkumab 200 mg Q8W; all patients were maintained on concomitant methotrexate (10 25 mg/week). 84 At week 28, there were no significant differences in the proportion of patients achieving ACR 20 responses in the combined ustekinumab group or combined guselkumab group, vs. placebo (53.6% and 41.4% vs. 40.0%; P and P , respectively). Compared to placebo, ustekinumab had a numerically higher percent improvement in number of tender and swollen joints and PGA of disease activity; guselkumab attained only modest improvements in these measurements. The study concluded that neither guselkumab nor ustekinumab had a significant impact on reducing the signs and symptoms of RA. 84 Safety. In VOYAGE-1, there were similar proportions of patients reporting at least one AE across all treatment arms in the placebo-controlled period, with nasopharyngitis and URI the most common. Through week 48, guselkumab and adalimumab demonstrated similar safety profiles in terms of common AEs (i.e., nasopharyngitis, headache, arthralgia), neutropenia, candidiasis, study discontinuation rates, SAEs, serious infection rates, and MACEs. Patients in the guselkumab arm had two malignancies (prostate and breast), whereas adalimumab had none. Adalimumab was associated with higher rates of injection site reactions (9.0% vs. 2.2%). No cases of IBD were reported throughout the study, suggesting a protective role of IL-23 inhibition in intestinal inflammation. 80 Similar safety data were obtained from the VOYAGE-2 trial. 81 In the NAVIGATE trial, AEs were reported in 64.4% of patients on guselkumab and 55.6% exposed to ustekinumab. SAEs occurred in 6.7% and 4.5% of patients on guselkumab and ustekinumab, respectively, including three myocardial infarctions (guselkumab, two; ustekinumab, one) and two malignancies in the guselkumab arm (bladder cancer and fatal squamous cell carcinoma). 82 Comparable safety profiles between these agents were also observed in the phase II RA study. Overall, ustekinumab was associated with more gastrointestinal AEs (9.1%), and guselkumab with blood and lymphatic disorders (9.3%). SAE rates were low and similar across treatment groups VOLUME 103 NUMBER 1 JANUARY