New and Emerging Therapies in Craig L. Leonardi, MD,* and Kenneth B. Gordon, MD†

As the Figure illustrates, blockade of IL-12 results in down- n Abstract regulation of a type 1 response and a consequent decrease in This article discusses the scientific rationale for the use of production of interferon-γ and TNF-α. Blockade of IL-23 results inhibitors, including , an inhibitor in downregulation of T-helper (T )17 and T 22 responses, of the (IL)-12 and IL-23 pathways in psoriasis. H H Also addressed are the efficacy and safety data for this reducing levels of a number of , including IL-17, all 1 agent, as well as for several emerging therapies that target their isoforms including A and F, as well as TNF-α. other cytokine pathways in psoriasis: the IL-17 inhibitors It is known that production of IL-17 cytokines is increased , , and , the IL-23 in psoriatic skin, induces neutrophilia, and enhances both blocker tildrakizumab, and the small-molecule kinase inflammation and angiogenesis. IL-22 levels correspond to inhibitors apremilast (a phosphodiesterase-4 blocker) and tofacitinib (a inhibitor). disease activity. In psoriasis, IL-22 levels are increased in both Semin Cutan Med Surg 33(supp2):S37-S41 skin and plasma, and IL-22 is known to induce keratinocyte © 2014 published by Frontline Medical Communications hyperproliferation.1 n Keywords Ustekinumab Apremilast; brodalumab; interleukin-12/23 inhibitors; The IL-12/23 inhibitor ustekinumab, a subcutaneously interleukin-17 inhibitors; ixekizumab; JAK; Janus kinase inhibitors; phosphodiesterase-4 inhibitors; psoriasis administered agent, was approved by the US Food and Drug treatment; secukinumab; tildrakizumab; tofacitinib; tumor Administration (FDA) in 2009 for the treatment of patients necrosis factor inhibitors; ustekinumab 18 years of age or older with moderate to severe plaque psori- asis who are candidates for phototherapy or systemic therapy. eveloped and introduced within the last 5 years, agents The Psoriasis Followed by Long-Term Extension (PHOENIX) studies, two phase III multicenter, randomized, double-blind, that block inflammatory pathways other than tumor placebo-controlled trials, were the pivotal trials that led to the necrosis factor (TNF) represent new options for treating D approval of the drug for psoriasis.* The PHOENIX 1 study is psoriasis (Table). Among them are ustekinumab, a monoclonal discussed below. The results of a recently completed phase III antibody that targets the p40 subunit that is shared by IL-12 trial of ustekinumab (PSUMMIT 1) led to the approval of this 1 and IL-23 (IL-12/23) ; three IL-17 inhibitors—secukinumab, agent for psoriatic arthritis.2 ixekizumab, and brodalumab; the IL-23 blocker tildrakizumab; and two small molecules that target the kinase pathway— PHOENIX 1 Study apremilast a (phosphodiesterase-4 [PDE-4] inhibitor) and PHOENIX 1 was an efficacy study of long-term use of 3 tofacitinib (a Janus kinase [JAK] inhibitor). ustekinumab for up to 76 weeks. A randomized-withdrawal design was used (described below); the primary end point was * Clinical Professor of Dermatology, Saint Louis University/Central the proportion of patients who achieved a 75% improvement Dermatology, St Louis, MO. in the Psoriasis Area Severity Index (PASI 75) from baseline. † Professor of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL. Chief among the secondary end points were the proportion Publication of this CME article was jointly sponsored by the University of patients determined to be clear or minimal at week 12, as of Louisville School of Medicine Continuing Medical Education and well as time to loss of the PASI 75 response in the group on Global Academy for Medical Education, LLC, and is supported by maintenance therapy compared to the group withdrawn from educational grants from AbbVie, Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Amgen Inc., and Celgene Corporation. treatment at week 40. The 766 patients in the study were randomized into three Dr Leonardi and Dr Gordon have received an honorarium from Global Academy for Medical Education for their participation in groups (in a 1:1:1 ratio) to receive ustekinumab 45 mg, this activity. They acknowledge the editorial assistance of Joanne ustekinumab 90 mg, or placebo at weeks 0 and 4, and then Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Joanne every 12 weeks thereafter. At week 12, the patients who had Still has no relevant financial relationships with any commercial interests. been assigned to the placebo group at baseline were crossed Kenneth B. Gordon, MD, has been a consultant and/or investigator over to receive ustekinumab 45 mg or ustekinumab 90 mg at for AbbVie, Amgen, Celgene, Janssen Biotech, Inc., Merck & Co., Inc., weeks 12 and 16, and then every 12 weeks thereafter.3 Novartis, and Pfizer Inc. At week 28, patients who had not achieved a 50% improvement Craig L. Leonardi, MD, has been a consultant and/or investigator and/ on the PASI (PASI 50) discontinued ustekinumab. Those who or speaker and/or advisory board member for AbbVie, Amgen, Anacor Pharmaceuticals Inc., Celgene, Janssen Biotech, Eli Lilly, Galderma had achieved PASI 50 but had a response less than PASI 75 at Laboratories, L.P., GlaxoSmithKline, Incyte Corporation, LEO Pharma, either week 28 or 40 began a dosage schedule of every 8 weeks.3 Maruho Co., Ltd., Novartis, Novo Nordisk Inc., Pfizer, Schering-Plough, Sirtis Pharmaceuticals, Inc., Stiefel Laboratories, Inc., Tolmar Inc., *Both ustekinumab and are IL-12/23 inhibitors that were demon- Vascular Biogenics Ltd., and Warner Chilcott LTD. strated to be effective in phase III clinical trials in patients with psoriasis. Address reprint requests to: Craig L. Leonardi, MD, Central However, because of unresolved safety concerns (cardiovascular events, Dermatology, 1034 S. Brentwood Boulevard, St. Louis, MO 63117; squamous cell carcinoma, and serious infections) that emerged in the studies [email protected]. of briakinumab, further development of this agent currently is on hold. 1085-5629/13/$-see front matter © 2014 Frontline Medical Communications DOI: 10.12788/j.sder.0071 Vol. 33, No. 2S, March 2014, Seminars in Cutaneous Medicine and Surgery S37 n n n New and Emerging Therapies in Psoriasis

At week 40, patients who had been randomized to had 96% improvement at week 40, and, by week 64, this rate ustekinumab at baseline and who had achieved a PASI 75 had dropped to about 40%. The median time to loss of PASI 75 response at week 28 or 40 were randomized again to one of response was approximately 15 weeks. No cases of rebound two groups: half received ustekinumab every 12 weeks (main- (rapid recurrence of symptoms) occurred in this trial.3 tenance therapy) and the other half received placebo. In those randomized to the placebo group at week 40 who subse- IL-12/23 Safety Data quently lost at least 50% of the PASI improvement achieved Several important, potentially drug-related serious adverse at week 40, treatment with ustekinumab was reinstituted on events were seen in the phase III trials of ustekinumab in 3 4 their previous regimen (interrupted therapy).3 psoriasis—both PHOENIX 1 and PHOENIX 2 —including Efficacy. At week 12, significantly more patients in both infection, cancer, cardiovascular issues, and death. Among the 45-mg and the 90-mg treatment groups had achieved the patients who received 45 mg of ustekinumab, one case each of primary end point—PASI 75—than did those in the placebo angina and stroke occurred. Among those who received 90 mg group (P<0.0001). Specifically, PASI 75 was achieved at week of ustekinumab, the infections were two cases of cellulitis and 12 by 67% of patients in the 45-mg treatment arm (n=255), 66% one case of disseminated herpes zoster. At that same dosage of those in the 90-mg group (n=256), and 3% of those who level, one patient underwent coronary artery bypass surgery received placebo (n=255). Patients who had been randomized and one patient died. The single fatality was an unwitnessed to the placebo group initially achieved similar results in the death that was determined to result from congestive cardio- crossover phase of the trial.3 myopathy in a patient who had had symptoms several months Rapid onset of efficacy was an important finding in this prior to the start of the study. study, as was long duration of improvement. At week 40, the Recently, Papp and colleagues 5 presented 5-year postmar- long-term responders were randomized to either withdrawal or keting surveillance data on 3,117 patients with a total of 8,998 maintenance groups. Through year 1, persistence of PASI 75 patient years of experience: 3,766 patient years of experience (that is, time to loss of the PASI 75 response) was significantly with the 45-mg dose of ustekinumab and 5,232 patient years of better in the patients on maintenance therapy than in those experience with the 90-mg dose. in whom treatment was withdrawn (P<0.0001). In addition, The events of interest in the 5-year cumulative data (through those on maintenance therapy maintained PASI 50, PASI 75, 2011) included serious infections (1.10/100 patient years [95% PASI 90, and Physician Global Assessment responses up to at CI, 0.89-1.14]), nonmelanoma skin cancer (0.52/100 patient least week 76.3 years [95% CI, 0.39-0.70]), malignancy other than nonmela- Decline following cessation of therapy in the withdrawal noma skin cancer (0.60/100 patient years [95% CI, 0.45-0.78]), groups began gradually after 4 weeks (ie, by week 44); the rate and major adverse cardiovascular events (MACE) (0.44/ of decline accelerated after week 52. The withdrawal groups 100 patient years [95% CI, 0.32-0.61]).5 n TABLE Biologic Agents and Small Molecules in Psoriasis

Class/Target Pathway Generic Drug Name Current Status*

Biologic agents

TNF-α inhibition Approved for psoriasis, 2008

Etanercept Approved for psoriasis, 2004

Infliximab Approved for psoriasis, 2006

IL-12 and IL-23 inhibition Ustekinumab Approved for psoriasis, 2008

Direct inhibition of IL-17 Brodalumab Phase III trials under way

Ixekizumab Phase III trials under way

Secukinumab Phase III trials complete

IL-23 blocker Tildrakizumab Phase III trials under way

Small molecules

PDE-4 inhibitor Apremilast Approved for psoriasis arthritis, 2014

JAK inhibitor Tofacitinib Phase III trials complete

IL=interleukin; JAK=Janus kinase; PDE-4=phosphodiesterase-4; TNF=tumor necrosis factor. *The status listed for each agent is current as of March 1, 2014.

S38 Seminars in Cutaneous Medicine and Surgery, Vol. 33, No. 2S, March 2014 Craig L. Leonardi, MD, and Kenneth B. Gordon, MD

IL-12/23 inhibitors}•Ustekinumab

•Adalimumab IL-12 IL-23}•Tildrakizumab •Etanercept TNF inhibitors •Infliximab IL-6 Kinase inhibitors •Apremilast T 1 H TH2 •Tofacitinib

TH17 IL-6

TNF •Brodalumab IL-17A •Ixekinumab anti-IL-17A •Secukinumab

Dendritic cell Macrophage Neutrophil Th17 cell Mast cell Target cell n FIGURE Current Approaches to Therapeutic Pathways in Psoriasis. TNF inhibitors prompt broad inhibitory immune responses in both innate and adaptive pathways. IL-12/23 inhibitors block T-cell differentiation and also have broad inhibitory activity. Small-molecule kinase inhibitors/immunomodulators exert inhibitory action within immune and other cell types. IL-17R inhibitors act at the level of the cytokine receptor. IL-17A inhibitors affect only IL-17A signaling, thus preserving other functions. IL=interleukin; TH=T helper; TNF=tumor necrosis factor. Sources: Adapted from Garber K. Psoriasis: From bed to bench and back. Nat Biotechnol. 2011;29:563-566; Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment.Nat Rev Drug Discov. 2010;9:703-718.

A comparison of the year-by-year data over this same time to MACE risk.7 Thus, clinicians are advised to consider all period (2007 through 2011) shows that the number of serious options in selecting biologic treatment. As Kerdel and Strober8 adverse events decreases with time.5 discussed in their article on page 31S of this supplement, the With regard to MACE, specifically—that is, heart attack, TNF inhibitors have a cardioprotective effect, and patients stroke, or cardiovascular death due to heart attack or stroke— with psoriasis have an increased incidence of cardiovascular the data on ustekinumab are fairly constant over the years. risk factors. Additional experience with these agents over time However, during the first year of experience with ustekinumab will help clarify the significance of some of the safety signals (the period covering the phase III trials), a small increase was that have been seen in the clinical studies to date. seen in MACE, particularly in the first 12 weeks. This increase IL-12/23 Inhibitor vs Anti-TNF Biologic was then followed by a reduction in MACE events, suggesting In the first head-to-head trial of biologic agents in psoriasis, that by reducing systemic inflammation, improvement in Griffiths and colleagues9 compared the anti-TNF agent etan- cardiovascular status occurred.5 ercept to ustekinumab in 903 patients with moderate to severe An analysis of the cumulative data from the controlled trials psoriasis in the Active Comparator (CNTO 1275/Enbrel) of ustekinumab, briakinumab, and three TNF inhibitors (inflix- Psoriasis Trial (ACCEPT). Patients were randomly assigned imab, etanercept, and adalimumab) showed that a total of to receive subcutaneous injections of high-dose etanercept 10 events occurred during active treatment with the IL-12/23 (50 mg twice weekly for 12 weeks) or ustekinumab, either 45 mg inhibitors vs none in the placebo groups.6 Statistically, using the or 90 mg, at weeks 0 and 4. The primary end point was the pro- Mantel-Haenszel method, the difference in MACE between the portion of patients who achieved PASI 75 or greater at week 12. active-treatment and placebo populations was not significant At week 12, 56.8% (n=347) of patients who received etaner- (P=0.11). In the TNF-inhibitor trials, one event was seen in the cept had PASI 75 improvements or greater. In the ustekinumab active-treatment and one occurred in the placebo group (P=0.94). groups, 67.5% (n=209) of those who received 45 mg had It is important to note that the clinical trials were not powered a PASI 75 score (superiority vs etanercept, P=0.012), and to detect rare events and that statistical analyses performed on 73.8% (n=347) of patients in the 90-mg dosage group achieved the same data sets have yielded conflicting results with respect PASI 75 (superiority vs etanercept, P<0.001).9

Vol. 33, No. 2S, March 2014, Seminars in Cutaneous Medicine and Surgery S39 n n n New and Emerging Therapies in Psoriasis

IL-17 Inhibitors A significantly better outcome was seen with the fixed monthly As discussed above, IL-17 production is an important cyto- 300-mg dosage than with the other three dosage regimens.12 kine in psoriasis pathogenesis, and IL-12/23 blockade (as with Although these efficacy data are impressive, the full analyses ustekinumab) results in downregulation of TH17 and TH22 of safety data from the phase III studies are not yet available. responses.1 Another approach is to target IL-17 directly, either No specific safety concerns have been identified to date, but with antibodies against specific subtypes of IL-17, IL-17A, attention will be on the rate of infections seen, especially or IL-17F or by blocking the entire family of IL-17 through infections that are known to be IL-17 dependent (in particular, blockade of a common receptor subunit. Both of those strat- localized infections with Staphylococcus aureus and Candida egies are being incorporated in new agents. Two of these species). In addition, it is known that the class of anti-IL-17 (secukinumab and ixekizumab) bind and eliminate IL-17A. drugs causes a decrease in neutrophil counts, although this is Brodalumab blocks the entire IL-17 population by blocking reversible on discontinuation of the medication. the IL-17A receptor. Ixekizumab Secukinumab In the ixekizumab phase II of patients with Secukinumab is the first of the IL-17 antibody biologics to moderate to severe plaque psoriasis, Leonardi et al13 found complete phase III studies; the results of three of these trials— that after 12 weeks of injections (at 0, 2, 4, 8, and 12 weeks) Efficacy and Safety of Subcutaneous Secukinumab for of various doses of ixekizumab (10, 25, 75, or 150 mg), the Moderate to Severe Chronic Plaque-Type Psoriasis for Up to percentage of patients who achieved PASI 75 was significantly 1 Year (ERASURE),10 Full Year Investigative Examination greater than that in the placebo group for all dosages except the of Secukinumab vs Etanercept Using 2 Dosing Regimens to lowest. PASI 75 scores were achieved by 82.1% of patients in Determine Efficacy in Psoriasis (FIXTURE),11 and Study the 150-mg ixekizumab group, by 82.8% of those who received Comparing Secukinumab Use in Long-Term Psoriasis 75 mg of the drug, and by 76.7% of patients in the group who Maintenance Therapy: Fixed Regimens vs Re-treatment Upon received the 25-mg dose; in contrast, 7.7% of patients in the Start of Relapse (SCULPTURE)12—were presented at the 22nd placebo group achieved PASI 75 (P<0.001 for each treatment Annual Congress of the European Academy of Dermatology group comparison). and Venereology in Istanbul, Turkey. Secukinumab (previously In addition, the percentages of patients who achieved PASI 90 called AIN457) targets IL-17A. or greater or PASI 100 were as follows: 71.4% and 39.3%, In the ERASURE study, the objective was to establish effi- respectively, in the 150-mg treatment group, and 58.6% and cacy, safety, and tolerability of two doses of secukinumab 37.9%, respectively, in the 75-mg treatment group. Half of the (150 and 300 mg) compared to placebo at 12 weeks and up to patients (50.0%) who received 25 mg of ixekizumab achieved 52 weeks. PASI 75 was achieved at week 12 in 81.6% of the PASI 90 after 12 weeks. No patients in the placebo group patients who received 300 mg of secukinumab, 71.6% of those achieved PASI 90 or greater, a statistically significant differ- who received 150 mg of the drug, and 4.5% of those in the ence compared to the results in the treatment arms (P<0.001 placebo group (P<0.0001 for both active treatment groups vs for these comparisons). These differences were seen as early the placebo group).10 as week 1 (for the two highest doses) and persisted through 13 In the FIXTURE trial, patients were randomized to receive week 20. Phase III studies currently are under way. either 150 or 300 mg of secukinumab, 50 mg of etanercept, or Brodalumab placebo. The primary end points were percentage of patients The second anti-IL-17 drug now in phase III clinical trials is achieving PASI 75 or greater at week 12 and improvement on brodalumab (previously called AMG 827), which blocks the the Investigator’s Global Assessment. PASI 75 was achieved at receptor as well as IL-17A, IL-17F, and IL-17C. In a 12-week week 12 by 77.1% of patients who received secukinumab 300 mg phase II clinical trial in patients with moderate to severe and 67% of those who received 150 mg; in the etanercept group, plaque psoriasis,14 198 patients were randomly assigned to 44% of patients achieved PASI 75, and 4.9% of patients in the receive placebo, one of three doses of brodalumab (70, 140, or placebo group had a PASI 75 response.11 210 mg/day) on day 1 and at weeks 1, 2, 4, 6, 8, and 10, The SCULPTURE trial was designed to determine whether or 280 mg monthly. The primary end point was percentage of as-needed dosing of secukinumab would be effective in patients improvement in PASI over baseline at week 12. In this study, who had responded to a course of induction therapy with the achievement of PASI 75 or greater was a secondary end point. drug. Patients who achieved a response of PASI 75 or greater on Significant improvements in PASI were seen in all treatment either 150 or 300 mg of secukinumab were rerandomized at week groups compared to placebo (P<0.001). Improvements of 8 to receive either maintenance therapy (monthly injections of PASI 75 or greater were seen in 77% of patients who received the same dose they had been on since baseline) or re-treatment as 140 mg of brodalumab and in 82% of those who received 210 mg; needed when relapse occurred (ie, loss of PASI 75 response and no patients in the placebo group achieved PASI 75, a significant a decrease of 20% or more from the maximum PASI improve- difference for both doses (P<0.001). In addition, 72% of those ment achieved over baseline). At week 52, 78.2% of the patients who received 140 mg of the drug achieved PASI 90 or greater, as who received monthly injections of secukinumab 300 mg had did 75% of those who received 210 mg of brodalumab.14 maintained at least PASI 75, and 67.7% of those in the group Although a high level of efficacy has been demonstrated so who received 300 mg of secukinumab on an as-needed basis had far in ixekizumab and brodalumab clinical trials, it is impor- PASI 75 at week 52. In the patients who received 150 mg of tant to remember that these results are from phase II studies; secukinumab, 62.1% maintained PASI 75 at week 52 with month- conclusions about efficacy and safety await results from the ly dosing, as did 52% of those in the as-needed dosing group. phase III studies, now under way.

S40 Seminars in Cutaneous Medicine and Surgery, Vol. 33, No. 2S, March 2014 Craig L. Leonardi, MD, and Kenneth B. Gordon, MD

IL-23 Inhibitor At week 12, significantly higher rates of PASI 75 improve- Tildrakizumab (previously named MK3222) is a humanized ments were seen in all three active-treatment groups than in that blocks the p19 subunit of IL-23. the placebo group: 66.7% of the 15-mg twice-daily group In a randomized, double-blind, placebo-controlled, parallel- (P<0.0001), 40.8% of the 5-mg group (P<0.0001), and 25.0% group phase IIb trial in 355 adults with moderate to severe of the 2-mg group (P<0.001) compared with placebo. psoriasis, four doses of subcutaneous tildrakizumab (5, 25, 100, The phase II data show that in patients with psoriasis, and 200 mg) were compared with placebo.15 In part 1 of the tofacitinib was generally safe and well tolerated, but certain study (16 weeks), injections were administered at weeks 0 and 4. adverse events are of interest—primarily, decreases in hemo- The primary end point, mean change in PASI from baseline to globin levels, changes in lymphocyte counts, and increased week 16, was significantly greater in all dose groups than in the rates of infections seen especially at the higher (and more placebo group (P≤0.001 for all comparisons). Improvements of effective) treatment dosages. Until the results and analyses of PASI 75 were seen in 76.2% of patients who received 200 mg, the phase III clinical trials are available, conclusions about the in 67.1% of patients who received 100 mg, in 65.5% of those risk-benefit profile of tofacitinib in psoriasis are pending. who received 25 mg, and in 35.0% of patients who received Conclusion 5 mg. In contrast, 4.9% of patients in the placebo group Currently, many patients with moderate to severe psoriasis are achieved PASI 75. benefiting from biologic therapy with several TNF inhibitors In part 2 of the study, patients who achieved at least a and the IL-12/23 agent ustekinumab. Other biologic agents (the PASI 75 response continued to receive injections every IL-17 inhibitors secukinumab, ixekizumab, and brodalumab and 12 weeks to week 52.16 Patients who received 5-mg and 25-mg the IL-23 inhibitor tildrakizumab) also may soon be available. doses of tildrakizumab continued with no dose change. Two small-molecule kinase inhibitors, apremilast and tofacitinib, Patients who had received the higher doses of tildrakizumab have completed phase III trials. Tofacitinib is being considered (100 and 200 mg) were rerandomized, in a 1:1 ratio, to either for approval by the FDA, and apremilast was approved by the maintain or reduce their previous dose. At week 52, the week FDA in March 2014 for the treatment of psoriatic arthritis. 16 PASI 75 responders who continued on their previous doses These advances resulted largely from the newer understanding of tildrakizumab showed no loss of efficacy from week 16 to of pathophysiology that has developed within the past decade. week 52. The group whose dose was reduced from 200 mg to 100 mg showed a small decrease in response from peak; References 1. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: the group whose dosage was reduced from 100 mg every Recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9:461-467. 12 weeks to 25 mg every 12 weeks showed the greatest loss of 2. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, PASI response from peak levels. double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382:780-789. Two phase III studies currently are under way. 3. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week Small Molecules results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674. A number of agents classified as small molecules are in the 4. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a early stages of development. Recently, two of these drugs— human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). apremilast, a PDE-4 inhibitor, and tofacitinib—have completed Lancet. 2008;371:1675-1684. phase III trials. 5. Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: Final results from 5 years of follow-up. Br J Dermatol. 2013;168:844-854. Apremilast 6. Ryan C, Leonardi CL, Krueger JG, et al. Association between biologic therapies The Evaluate Safety and Effectiveness of Oral Apremilast for chronic plaque psoriasis and cardiovascular events: A meta-analysis of ran- domized controlled trials. JAMA. 2011;306:864-871. (ESTEEM) 1 trial of apremilast, an oral medication, involved 7. Tzellos T, Kyrgidis A, Zouboulis CC. Re-evaluation of the risk for major adverse 844 patients who were randomized to receive apremilast, 30 mg cardiovascular events in patients treated with anti-IL-12/23 biological agents 17 for chronic plaque psoriasis: A meta-analysis of randomized controlled trials. twice daily or placebo. The investigators reported that 33.1% J Eur Acad Dermatol Venereol. 2013;27:622-627. of those treated with apremilast achieved at least PASI 75 at 8. Kerdel FA, Strober BE. Tumor necrosis factor inhibitors in psoriasis: An update. Semin Cutan Med Surg. 2014;33(suppl 2):S31-S36. week 16 of the trial, and 58.7% achieved at least PASI 50 9. Griffiths CEM, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab (P<0.0001 for both groups vs placebo). Clearly, this medication and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362:118-128. 10. Elewski B et al. ERASURE study of secukinumab phase 3 study. Presented yields lower response rates than those seen with biologics, but at: 22nd Annual Congress of the European Academy of Dermatology and rates are comparable to those with other anti-inflammatory medi- Venereology; October 2-6, 2013; Istanbul, Turkey. 11. Langley R et al. Secukinumab compared with placebo and etanercept: The first cations such as methotrexate. Nonetheless, apremilast may be a 52-week head-to-head comparison of two biologics in a randomized, double-blind, good choice for patients with psoriasis who also have psoriatic phase 3 study in subjects with moderate-to-severe psoriasis. Presented at: 22nd Annual Congress of the European Academy of Dermatology and Venereology; arthritis (against which this drug has demonstrated efficacy) and October 2-6, 2013; Istanbul, Turkey. for those in whom an oral medication is preferred. Apremilast 12. Mrowietz U et al. Presented at: 22nd Annual Congress of the European Academy of Dermatology and Venereology; October 2-6, 2013; Istanbul, Turkey. was approved by the FDA in March 2014 for the treatment of 13. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal anti- psoriatic arthritis and is the first oral medication approved body ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366:1190-1199. 14. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti–interleukin-17– for this indication. Additionally, no clear need for monitoring of receptor antibody for psoriasis. N Engl J Med. 2012;366:1181-1189. this medication has been identified to date. 15. Thaci D et al. Presented at: 22nd Annual Congress of the European Academy of Dermatology and Venereology; October 2-6, 2013; Istanbul, Turkey. Tofacitinib 16. Reich K et al. Presented at: 22nd Annual Congress of the European Academy of Dermatology and Venereology; October 2-6, 2013; Istanbul, Turkey. The other agent in the small-molecule class to reach late-stage 17. Reich K et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with clinical evaluation, tofacitinib, is a signal transduction molecule moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled 18 trial (ESTEEM 1). Presented at: 71st Annual Meeting of the American Academy that blocks the JAK pathway. In a phase II trial, tofacitinib, of Dermatology; March 1-5, 2013; Miami Beach, FL. 18. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral an oral medication, was administered at three different dosages Janus kinase inhibitor, in the treatment of psoriasis: A phase 2b randomized (2, 5, or 15 mg twice daily), which were compared to placebo. placebo-controlled dose-ranging study. Br J Dermatol. 2012;167:668-677.

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