Anti Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article Anti Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis Craig Leonardi, M.D., Robert Matheson, M.D., Claus Zachariae, M.D., D.M.Sci., Gregory Cameron, Ph.D., Linda Li, M.S., Emily Edson-Heredia, M.P.H., Daniel Braun, M.D., Ph.D., and Subhashis Banerjee, M.D. A BS TR AC T From the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.); Oregon Medical Research Center PC, Portland (R.M.); Department of Dermato-Allergology, University Hospital of Copenhagen Gentofte, Hellerup, Denmark (C.Z.); and Lilly Research Laboratories, Eli Lilly (G.C., E.E.-H., D.B., S.B.), and Pharmanet/i3 (L.L.) both in Indianapolis. Address reprint requests to Dr. Leonardi at Central Dermatology PC, 134 S. Brentwood Blvd., Suite 6, St. Louis, MO 63117, or at leonardi@centralderm.com. N Engl J Med 12;366: Copyright 12 Massachusetts Medical Society. Background Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17a (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY ), a humanized anti interleukin-17 monoclonal antibody, for psoriasis treatment. Methods In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 1, 25, 75, or 15 mg of ixekizumab or placebo at, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 9% or by 1%. Results At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 1-mg dose) 15 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%) than with placebo (7.7%, P<.1 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 9%: 15 mg (71.4%), 75 mg (58.6%), and 25 mg (5.%) versus placebo (%, P<.1 for each comparison). Similarly, a 1% reduction in the PASI score was achieved in significantly more patients in the 15-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (%) (P<.1 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. Conclusions Use of a humanized anti interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT ) 119 n engl j med 366;13 nejm.org march 29, 12

2 Ixekizumab in Chronic Plaque Psoriasis Psoriasis vulgaris (plaque psoriasis) is a chronic, frequently painful, and often debilitating skin disorder. The estimated prevalence of diagnosed psoriasis in the United States is 3%, with approximately 17% of these patients having moderate-to-severe plaque psoriasis. 1 Psoriasis is characterized by inflammation and keratinocyte hyperproliferation 2 thought to be the pathological consequence of a T-cell mediated immune response to an as-yet unidentified autoantigen. Studies have shown that a subgroup of CD4+ T cells, type 17 helper T (Th17) cells, may play a specific pathological role in psoriasis. 3 Type 17 helper T cells secrete a number of proinflammatory cytokines, including interleukin-17a, a member of the proinflammatory interleukin-17 cytokine family. 4,5 Specific inhibition of interleukin-17a represents a novel, targeted approach to psoriasis treatment. Ixekizumab (LY ) is a humanized IgG4 monoclonal antibody that neutralizes interleukin- 17A (also known as interleukin-17). In a phase 2 study, we evaluated the safety and efficacy of ixekizumab administered subcutaneously in patients with chronic moderate-to-severe plaque psoriasis. Me thods Study Design This double-blind, multicenter, randomized, doseranging study was designed to evaluate the safety and efficacy of multiple subcutaneous doses of ixekizumab in patients with chronic moderate-tosevere plaque psoriasis, as defined in protocol (available with the full text of this article at NEJM.org). The protocol was approved by the investigational review board at each site. All patients provided written informed consent. The first patient visit occurred on April 19, 1; the last, on March 17, 11. The study was designed jointly by consultant experts in psoriasis and representatives of the sponsor, Eli Lilly. Data were collected by the investigators, gathered by Parexel International, and analyzed by the sponsor. All authors contributed to the interpretation of and vouch for the accuracy and completeness of the data. The principal investigator and coauthors from the sponsor wrote the manuscript, with medical writing support paid for by the sponsor. All authors made the decision to submit the manuscript for publication. The investigators, participating institutions, and sponsor agreed to maintain confidentiality of the data. Study Patients Eligibility criteria were an age of 18 years or older, chronic moderate-to-severe plaque psoriasis for at least 6 months before randomization, scores of at least 12 on the psoriasis area-and-severity index (PASI, on which scores range from to 72, with higher scores indicating more severe disease) 6 and at least 3 on the static physician s global assessment (on which scores range from [clear of disease] to 5 [severe disease]) at the screening and baseline visits, and psoriasis involving at least 1% of body-surface area at the screening and baseline visits. Exclusion criteria were the presence of nonplaque psoriasis, a clinically significant flare of psoriasis during the 12 weeks before randomization, an active infection within 5 days before administration of study drug, a recent serious systemic or local infection requiring hospitalization or antibiotic therapy, receipt of conventional systemic psoriasis therapy or phototherapy within the previous 4 weeks, receipt of topical psoriasis treatment within 2 weeks before randomization, or use of any biologic agent recently or concurrently with drug. Patients were randomly assigned to receive subcutaneous injections of placebo or 1 mg, 25 mg, 75 mg, or 15 mg of ixekizumab at, 2, 4, 8, 12, and 16 weeks. Patients were permitted to use topical moisturizers or emollients, bath oils, oatmeal bath preparations, or topical salicylic acid preparations for skin conditions during, as needed. Other medications could be used as medically necessary. Weak topical steroids (class VI or VII only) were permitted for use limited to the face, axillae, or genitalia as required. Topical medications were to be discontinued approximately 24 hours before visits requiring PASI assessments. No other topical preparations were allowed in the 2 weeks before randomization or during unless medically required to treat an adverse event. End Points The primary objective was to test whether ixekizumab treatment was superior to placebo, as measured by the proportion of patients who achieved a reduction in the PASI score by at least 75% over baseline at 12 weeks, and to estimate the percentage of reduction in the PASI score in each treatment group, by means of regression techniques. The PASI score combines assessments of the extent n engl j med 366;13 nejm.org march 29,

3 T h e n e w e ngl a nd j o u r na l o f m e dic i n e of involvement of body-surface area in psoriasis on four anatomical regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration or infiltration (thickness) in each region, yielding an overall score of for no psoriasis to 72 for the worst possible psoriasis. 6 Secondary end points included reduction in the PASI score by at least 9% or by 1% over baseline; the score on the static physician s global assessment, which is used to grade psoriasis lesions at a given time point (with for clear of disease and 5 for severe disease); the joint-pain visualanalogue scale (VAS), which assesses joint pain from psoriatic arthritis reported by the patient (score range, [no pain] to 1 [severe pain]); the Nail Psoriasis Severity Index (NAPSI), which scores the nail matrix and nail bed of each finger and toe (score range, [no nail psoriasis] to 16 [worst possible nail psoriasis]); and the Psoriasis Scalp Severity Index (PSSI), which yields a composite score of erythema, induration, and desquamation of scalp lesions and the extent of the scalp area involved (range, [no psoriasis] to 72 [worst possible scalp psoriasis]). These end points were ascertained at baseline and at 1, 2, 4, 6, 8, 12, 16, and weeks. Two additional secondary end points (both patient-reported) were collected only at weeks, 8, and 16: an itch VAS (on which scores range from [no itching] to 1 [severe itching]) and the Dermatology Life Quality Index (DLQI, on which scores ranging from to 3, with higher scores indicating worse health-related quality of life). 7 A 5-point change from baseline in the DLQI score is considered clinically relevant. 8 Adverse events were defined as those that first occurred or worsened after randomization. Adverse events and routine laboratory values were monitored and evaluated through weeks. Adverse events of special interest included allergic reactions or hypersensitivities, injection-site reactions, and infections. Laboratory abnormalities of special interest included cytopenias (leukopenia, neutropenia, and thrombocytopenia) and liver biochemical-test elevations (of alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase). Statistical Analysis Analyses of baseline characteristics included all randomly assigned patients. Efficacy analyses included patients who received at least one dose of drug and had at least one postbaseline efficacy assessment. Safety analyses were conducted on data from all patients who received the study drug. Missing data for the primary end point at 12 weeks were imputed by means of the last-observation-carried-forward method, whereby missing data points are replaced by the last available observation; in a separate analysis, missing data were imputed with the use of nonresponse imputation, in which patients who discontinued early, regardless of the status of response at the time of discontinuation, or who had a missing value at any time point had data imputed as a nonresponse at that time point. For the primary analysis, we expected to observe a reduction in the PASI score by at least 75% over a 12-week period in at least 7% of patients receiving the optimal ixekizumab dose and in 1% of patients receiving placebo. On this basis, we estimated that pairwise comparison of an ixekizumab group and the placebo group would have more than 99% power, with the use of a two-sided Fisher s exact test at the.5 significance level. The rates of reduction in the PASI score by at least 75% or 9% or by 1% and the scores on the static physician s global assessment were summarized for each group and compared between each study group and the placebo group. Numerical data, other than in the primary analysis, were analyzed by means of analysis of variance or covariance, and categorical data were analyzed with the use of the chi-square or Fisher s exact test. R esult s Study Patients For the 142 patients, baseline characteristics for the dosing groups were similar (Table 1). By weeks, 13 patients (9%) had discontinued treatment; the most common reason for discontinuation (in 4 [3%]) was development of an adverse event (Fig. 1). Concomitant topical glucocorticoids were used before the primary end point (at 12 weeks) in 1 patient in the 15-mg ixekizumab group, who used desoximetasone ointment from 8 to 1 weeks for an adverse event of contact dermatitis, as permitted in the protocol. Efficacy At 12 weeks, reduction in the PASI score by at least 75% (the primary outcome) or 9% occurred in significantly more patients in the 25-mg, 75-mg, and 15-mg ixekizumab groups (P<.1 for each vs. placebo) (Table 2 and Fig. 2). In addition, sig n engl j med 366;13 nejm.org march 29, 12

4 Ixekizumab in Chronic Plaque Psoriasis Table 1. Baseline Characteristics of the Patients, According to Study Group. Characteristic Placebo (N = 27) Ixekizumab P Value 1 mg 25 mg (N = 3) 75 mg (N = 29) 15 mg Age yr 45±13 48±11 46±15 46±13 46±13.96 Male sex no. (%) 14 (52) 16 (57) 18 (6) 19 (66) 14 (5).77 Weight kg 92±23 95±28 97±26 95±27 88±24.68 Duration of psoriasis yr 15±11 21±12 18±11 13±1 15±1.8 Previous systemic therapy no. (%) 13 (48) 12 (43) 9 (3) 6 (21) 1 (36).22 Body-surface area % 19±12 22±18 22±12 21±11 21±13.83 PASI score 16.5± ± ± ± ± spga score 3.3±.6 3.3±.5 3.4±.5 3.2±.5 3.3±.4.84 PSSI score 19.6± ±14.6.5± ± ± NAPSI score 35.± ± ± ± ± DLQI score 11.4± ± ± ± ± Plus minus values are means ±SD. P values are for the comparisons across all treatment groups and were calculated by means of analysis of variance for continuous variables and the chi-square test for categorical variables. Scores on the psoriasis area-and-severity index (PASI) range from to 72, with higher scores indicating more severe disease. Scores on the static physician s global assessment (spga) range from (clear of disease) to 5 (severe disease). Scores on Psoriasis Scalp Severity Index (PSSI) range from (no psoriasis) to 72 (worst possible scalp psoriasis). Scores are reported for the patients who had scalp psoriasis at baseline: 21 of the 27 patients in the placebo group, 21 of 28 patients in the 1-mg group, 24 of the 3 patients in the 25-mg group, 18 of the 29 patients in the 75-mg group, and 22 of the 28 patients in the 15-mg group. Scores on the Nail Psoriasis Severity Index (NAPSI) range from (no nail psoriasis) to 16 (worst possible nail psoriasis). Scores are reported for the patients who had nail psoriasis at baseline: 17 of the 27 patients in the placebo group, 13 of the 28 patients in the 1-mg group, 1 of the 3 patients in the 25-mg group, 1 of the 29 patients in the 75-mg group, and 1 of the 28 patients in the 15-mg group. Scores on the Dermatology Life Quality Index (DLQI) range from to 3, with higher scores indicating worse healthrelated quality of life. nificantly more patients in the 75-mg and 15-mg groups had a reduction in the PASI score by 1% (complete skin clearance) (P<.1 for each vs. placebo) (Table 2 and Fig. 2). When the data were analyzed with the use of nonresponse imputation, the results were identical to the results obtained by means of the last-observation-carried-forward method. In addition, significantly higher percentages of patients in the three highest ixekizumab dose groups had a static physician s global assessment score of (clear of disease) or of or 1 (minimal disease) (P<.5 for each dose and score group vs. placebo) (Table 2 and Fig. 2; and Fig. 1 in the Supplementary Appendix, available at NEJM.org). Significant differences between the two highest-dose groups and the placebo group were seen as early as 1 week in PASI scores, and significant differences between the 15-mg group and the placebo group were seen as early as 2 weeks in reduction in the PASI score by at least 75% and static physician s global assessment scores of or 1. Differences with the placebo group were sustained through weeks for all clinical measures (Fig. 2). Among patients with scalp psoriasis, significant reductions in the PSSI score were observed in the 25-mg, 75-mg, and 15-mg ixekizumab groups versus placebo at 12 weeks (Table 2 and Fig. 3) and were sustained through weeks. Among patients with nail psoriasis, significant reductions in the NAPSI scores were observed as early as 2 weeks in the 75-mg ixekizumab group versus placebo, and these effects were also sustained through weeks (Fig. 3). Among patients who reported having psoriatic arthritis, significant reductions from baseline were observed in the 15-mg ixekizumab group at 12 weeks (Table 2), as measured on the joint-pain VAS, and this reduction was sustained through weeks (not shown). Significant reductions in the mean (±SD) DLQI scores were detected at 8 weeks in the 15-mg ixekizumab group ( 7.8±5.7), the 75-mg ixekizumab group ( 8.5±5.1), and the 25-mg ixekizu- n engl j med 366;13 nejm.org march 29,

5 T h e n e w e ngl a nd j o u r na l o f m e dic i n e 142 Patients were enrolled and underwent randomization 27 Were assigned to receive placebo 28 Were assigned to receive subcutaneous ixekizumab, 1 mg 3 Were assigned to receive subcutaneous ixekizumab, 25 mg 29 Were assigned to receive subcutaneous ixekizumab, 75 mg 28 Were assigned to receive subcutaneous ixekizumab, 15 mg 4 Discontinued 1 Had adverse event 1 Withdrew 2 Had lack of efficacy 6 Discontinued 2 Had adverse events 2 Had protocol violations 1 Was lost to follow-up 1 Had lack of efficacy 1 Discontinued owing to adverse event 1 Discontinued owing to patient withdrawal 1 Discontinued owing to patient withdrawal 23 Completed 22 Completed 29 Completed 28 Completed 27 Completed Figure 1. Enrollment and Follow-up of the Study Patients through 12. mab group ( 7.1±6.5) as compared with placebo ( 2.4±4.4) (P<.1 for all comparisons). These significant reductions were sustained through 16 weeks (P<.1 for all comparisons). In addition, at 16 weeks, significantly more patients had a DLQI score of in the 15-mg, 75-mg, and 25-mg ixekizumab groups (39.3%, 37.9%, and 31.%, respectively) as compared with placebo (%, P<.5 for all comparisons). The 25-mg, 75-mg, and 15-mg treatment groups also had significant reductions in itch severity (VAS scores) as compared with the placebo group from 8 through 16 weeks (P<.1) (data not shown). Safety There were no reported serious adverse events, including deaths, in any group. The frequency of adverse events was similar between the combined ixekizumab groups and the placebo group (Table 3). The most common adverse events were nasopharyngitis, upper respiratory infection, injectionsite reaction, and headache. A total of four patients discontinued because of the following adverse events: hypertriglyceridemia (one patient receiving placebo), peripheral edema (one patient receiving 1 mg of ixekizumab), hypersensitivity (one patient receiving 1 mg of ixekizumab), and urticaria (one patient receiving 25 mg of ixekizumab). Across all four ixekizumab groups, six patients reported injection-site reactions; none were severe, and no patients discontinued treatment because of these reactions. There were no instances of anaphylactic reaction, angioedema, or major cardiovascular events (e.g., cardiovascular death, nonfatal myocardial infarction, or stroke). No serious infections, including mycobacterial or systemic fungal infections, were reported. There were no significant changes in mean absolute neutrophil counts with ixekizumab treatment. Neutropenia with a Common Terminology Criteria for Adverse Events (CTCAE) 9 grade of 2 (i.e., 1 to <15 cells per cubic millimeter) was observed in two patients (receiving either 75 mg or 15 mg of ixekizumab) with no reported symptoms; the lowest neutrophil count observed was 135 per cubic millimeter (Table 1 in the Supplementary Appendix). No obvious dose-related trend in infections or other adverse events was observed. In one patient in the ixekizumab 15-mg group with a history of treated basal-cell carcinoma, two new basal-cell carcinomas were detected during the treatment period. No other cancer was reported. Mean values for the serum transaminases alanine aminotransferase and aspartate aminotransferase and total and direct bilirubin showed no significant changes from baseline in any ixekizumab group, as compared with the placebo group, from 1 through weeks. Two patients in the 25-mg ixekizumab group had grade 3 or higher 1194 n engl j med 366;13 nejm.org march 29, 12

6 Ixekizumab in Chronic Plaque Psoriasis Table 2. Study End Points at 12, According to Study Group. Variable Placebo (N = 26) Ixekizumab 1 mg 25 mg (N = 3) 75 mg (N = 29) 15 mg PASI score 13.5± ±1. 4.5± ± ±4.2 Reduction in PASI score no. (%) By 75% 2 (8) 8 (29) 23 (77) 24 (83) 23 (82) By 9% 5 (18) 15 (5) 17 (59) (71) By 1% 5 (17) 11 (38) 11 (39) spga score no. (%) or 1 2 (8) 7 (25) 21 (7) 21 (72) (71) 2 (7) 6 () 11 (38) 13 (46) NAPSI % change from baseline 6.8± ± ± ± ±35.9 PSSI % change from baseline 3.5± ± ± ± ±41.5 Joint-pain VAS score change from baseline 4.8± ± ± ± ±27.5 Plus minus values are means ±SD. The data shown were analyzed by means of the last-observation-carried-forward method. Analysis with the use of nonresponse imputation gave similar results. All P values were calculated with the use of a two-sided Fisher s exact test, except for percent change in NAPSI and PSSI scores and change in scores on the joint-pain visual analogue scale (VAS), for which analysis of covariance was used. One of the 27 patients in the placebo group who received one dose of the placebo did not have any post-baseline assessments and was excluded from all efficacy analyses. P.1 versus placebo. P<.5 versus placebo. NAPSI data are reported for the patients who had nail psoriasis at baseline: 17 of the 27 in the placebo group, 13 of the 28 patients in the 1-mg group, 1 of the 3 patients in the 25-mg group, 1 of the 29 patients in the 75-mg group, and 1 of the 28 patients in the 15-mg group. P.1 versus placebo. PSSI data are reported for the patients who had scalp psoriasis at baseline: 21 of the 27 patients in the placebo group, 21 of the 28 patients in the 1-mg group, 24 of the 3 patients in the 25-mg group, 18 of the 29 patients in the 75-mg group, and 22 of the 28 patients in the 15-mg group. Scores on the joint-pain VAS range from (no pain) to 1 (worst pain possible). VAS data are reported for the patients who had psoriatic arthritis at baseline: 4 of the 27 patients in the placebo group, 7 of the 28 patients in the 1 mg group, 11 of the 3 patients in the 25-mg group, 8 of the 29 patients in the 75-mg group, and 8 of the 28 patients in the 15-mg group. The baseline means were 37.±28.5 in the placebo group, 4.4±3. in the 1-mg group, 34.9±32.1 in the 25-mg group, 35.2±19.4 in the 75-mg group, and 45.±27.4 in the 15-mg group. elevations of creatine kinase and aspartate aminotransferase (one also had a grade 3 elevation of alanine aminotransferase) that increased from the time of the screening visit or baseline without associated symptoms. These elevated enzyme levels decreased over time, and both patients continued ixekizumab treatment, while total and direct bilirubin and alkaline phosphatase levels remained normal throughout. Discussion The results of this study demonstrate that neutralization of interleukin-17 with the humanized monoclonal antibody ixekizumab may be an effective treatment for patients with chronic moderateto-severe plaque psoriasis. At 12 weeks, significant and dose-dependent increases were seen in the proportions of patients receiving ixekizumab who had a reduction in the PASI score by at least 75% or 9% or by 1% as well as in the proportions of patients who had a static physician s global assessment score of or of or 1. These reductions were sustained through weeks. Consistent with these clinical improvements, DLQI scores and itching severity also significantly decreased with ixekizumab treatment. Ixekizumab had a rapid onset of action, as evidenced by significant reductions in PASI scores, as compared with placebo, occurring at as early as week 1 in the two highest-dose groups and by the significantly higher percentage of patients with a reduction in the PASI score by at least 75% or static physician s global assessment score of or 1, as compared with placebo, at as early as week 2 in the highest-dose group. Approximately 4% n engl j med 366;13 nejm.org march 29,

7 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Placebo (N=26) 1-mg ixekizumab (N=28) 25-mg ixekizumab (N=3) 75-mg ixekizumab (N=29) 15-mg ixekizumab (N=28) A Patients with 75% Reduction in PASI Score Patients (%) B Patients with 9% Reduction in PASI Score Patients (%) C Patients with 1% Reduction in PASI Score 1 Patients (%) D Patients with spga Score of or Patients (%) Figure 2. Time Course of Clinical Responses as Measured by the Psoriasis Area-and-Severity Index (PASI) and Static Physician s Global Assessment (spga) through, According to Study Group. Shown are the percentages of patients who had reduction in the PASI score by at least 75% (Panel A), at least 9% (Panel B), and 1% (Panel C), respectively. Panel D shows the percentage of patients who had an spga score of (clear of disease) or 1 (minimal disease). Asterisks indicate significant differences (P<.5) between each study group and placebo. Missing data were imputed by the last-observation-carried-forward method. Similar results were found with the use of nonresponse imputation (data not shown). of patients in the two highest dose groups had complete clearance of psoriasis plaques on the skin, as reflected by a reduction in the PASI score by 1% or a static physician s global assessment score of at 12 weeks. Although it is difficult to draw conclusions from cross-study comparisons, the magnitude and rapidity of the clinical responses compare favorably to responses to other available biologic compounds targeting tumor necrosis factor, T cells, or interleukin-12/23 p Although interleukin-23 can drive the maturation of type 17 helper T cells, 2 interleukin-17 and interleukin-23 have many independent effects. 14 For difficult-to-treat areas such as the scalp and nails, significant differences from placebo were observed with ixekizumab treatment. Improvements in scalp psoriasis (i.e., reductions in the PSSI score) were notable, because it is difficult to evaluate psoriasis on the scalp and a high rate of response to placebo has been shown in clinical trials. 15,16 In our evaluations of nail psoriasis according to the NAPSI, both fingernails and toenails were included. Because toenails grow more slowly than fingernails, a longer treatment duration than that used in this trial may be required to assess greater effects of the treatment on toenails. 17 No serious adverse events, including deaths, 1196 n engl j med 366;13 nejm.org march 29, 12

8 Ixekizumab in Chronic Plaque Psoriasis A NAPSI Score Mean Percent Change from Baseline 4 Placebo (N=16) 6 1-mg ixekizumab (N=13) 25-mg ixekizumab (N=1) 8 75-mg ixekizumab (N=1) 15-mg ixekizumab (N=1) B PSSI Score Mean Percent Change from Baseline Placebo (N=) 1-mg ixekizumab (N=21) 25-mg ixekizumab (N=24) 75-mg ixekizumab (N=18) 15-mg ixekizumab (N=22) Figure 3. Percent Change in Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) Scores through, According to Study Group. Mean percent changes from baseline are shown for the NAPSI score among patients with nail psoriasis at baseline (Panel A) and the PSSI score among patients with scalp psoriasis at baseline (Panel B). Asterisks indicate significant differences (P<.5) between each study group and placebo. were observed in any group. Our study was not large enough or of long enough duration to ascertain uncommon adverse events. Although infections were the most common type of adverse event, there were no dose-related trends in the incidence rate or severity of events. As with other subcutaneous biologic therapies, injection-site reactions were more frequent in patients receiving ixekizumab as compared with placebo; none of these reactions were severe or resulted in treatment discontinuation. Two patients in the 25-mg ixekizumab group had grade 3 or greater elevations in creatine kinase, aspartate aminotransferase, or alanine aminotransferase levels that returned to screening or baseline levels over time with continued ixekizumab treatment. No major cardiovascular events, mycobacterial infections, or systemic fungal infections were reported. The only cancers reported were two basal-cell carcinomas in one patient. Two of the 115 patients (1.7%) receiving ixekizumab had CTCAE grade 2 neutropenia (lowest observed level, 135 per cubic millimeter); neither patient had concurrent infection reported. No CTCAE grade 3 or 4 neutropenia was observed. Although interleukin-17 may have a role in neutrophil mobilization and homeostasis, 14 it is not clear whether there is an association between interleukin-17 inhibition and neutropenia in psoriasis. In a previous proof-of-concept study of ixekizumab in patients with moderate-to-severe plaque psoriasis, neutralization of interleukin-17 led to improvements both in clinical measures of disease and in pathologic features of psoriasis in skinbiopsy specimens, including reductions in acanthosis, keratinocyte proliferation, and dermal infiltration of lymphocytes and other inflammatory cells within 2 weeks. 18 These changes were accompanied by significant down-modulation of a broad array of genes in the skin from multiple inflammatory pathways. The results from the proof-of-concept and phase 2 studies with ixekizumab add further evidence that interleukin-17 is a central cytokine driving psoriasis pathogenesis. Interleukin-17 levels are known to be increased in psoriatic skin. 19 Increased interleukin-17 levels may enhance neutrophil migration and survival in the dermis,21 and drive angiogenesis. 22 In addition, in synergy with tumor necrosis factor α, interleukin-17 causes release of inflammatory cytokines Furthermore, in a trial exploring the efficacy of another investigational monoclonal antibody (AIN457) against interleukin-17, reductions in the PASI score were observed after a single dose. 27 More recently, it has been shown that neutralization of the interleukin-17 receptor with monoclonal antibody AMG827 resulted in significant clinical improvements, consistent with the results of this study. 28 n engl j med 366;13 nejm.org march 29,

9 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 3. Adverse Events during the Study Period (through ), According to Study Group. Variable Placebo (N = 27) Ixekizumab 1 mg 25 mg (N = 3) 75 mg (N = 29) 15 mg No. of adverse events No. of serious adverse events 1 Adverse event no. of patients (%) 17 (63) 21 (75) 21 (7) 17 (59) 13 (46) Adverse events no. of patients (%) Infection or infestation 7 (26) 12 (43) 9 (3) 9 (31) 8 (29) Nasopharyngitis 5 (19) 3 (11) 3 (1) 3 (1) 4 (14) Upper respiratory infection 1 (4) 1 (4) 3 (1) 1 (3) 1 (4) Injection-site reaction 3 (1) 1 (3) 2 (7) Headache 1 (4) 4 (14) 4 (13) 1 (3) 1 (4) Allergy or hypersensitivity 2 (7) 1 (4) 1 (3) 2 (7) 1 (4) Adverse events were those that first occurred or worsened after randomization. The specific events listed are those that occurred in at least 5% of patients receiving ixekizumab. Allergy or hypersensitivity was defined as that distinct from injection-site reactions. Allergy or hypersensitivity events include those described by reported terms that were consistent with hypersensitivity, on the basis of Medical Dictionary for Regulatory Activities Standard Medical Queries for anaphylactic reaction, angioedema, and severe cutaneous adverse reaction. Taken together, these data suggest that inhibition of interleukin-17 may be an effective and targeted therapy for psoriasis. Patients with chronic moderate-to-severe plaque psoriasis treated with ixekizumab had significant improvement in clinical measures during the 12-week treatment period that were rapid and sustained through weeks with continued treatment. Further studies are needed to establish the long-term safety and efficacy of ixekizumab in the treatment of psoriasis. Supported by Eli Lilly. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Damon Disch for his assistance with design; Pamela Boltz, Barbara Jackson, and Joseph Durrant of Pharmanet/i3 for editorial assistance on a previous draft of the manuscript; and David Shrom of Eli Lilly and Laura Bean Warner of Pharmanet/i3 for their assistance with manuscript preparation. References 1. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 3-4. J Am Acad Dermatol 9;6: [Erratum, J Am Acad Dermatol 9;61:57.] 2. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 7;9: Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 6;18:67-5. [Erratum, Curr Opin Immunol 7;19:111.] 4. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 5;5: Li J, Chen X, Liu Z, Yue Q, Liu H. Expression of Th17 cytokines in skin lesions of patients with psoriasis. J Huazhong Univ Sci Technolog Med Sci 7;27: Fredriksson T, Pettersson U. Severe psoriasis oral therapy with a new retinoid. Dermatologica 1978;157: Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19: Kimball AB, Krueger GG, Woolley JM. Minimal important differences for the dermatology life quality index (DLQI) in psoriasis patients. Presented at the meeting of the American Academy of Dermatology, New York, July 28 August 1, 4. (Poster.) 9. Common Terminology Criteria for Adverse Events (CTCAE), version 3.. August 9, 6 ( Development/electronic_applications/ docs/ctcaev3.pdf). 1. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 3; 349: Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76- week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 1). Lancet 8;371: [Erratum, Lancet 8;371:1838.] 12. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52- week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 2). Lancet 8;371: Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 5;366: Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity 4;21: Tyring S, Mendoza N, Appell M, et al n engl j med 366;13 nejm.org march 29, 12

10 Ixekizumab in Chronic Plaque Psoriasis A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/ Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial. Int J Dermatol 1;49: van de Kerkhof PC, Franssen ME. Psoriasis of the scalp: diagnosis and management. Am J Clin Dermatol 1;2: Rigopoulos D, Gregoriou S, Lazaridou E, et al. Treatment of nail psoriasis with adalimumab: an open label unblinded study. J Eur Acad Dermatol Venereol 1; 24: Krueger J, Fretzin S, Farinas M, et al. Interleukin-17A is an essential cytokine to sustain pathogenic cell activation and inflammatory gene circuits in psoriasis vulgaris. Br J Dermatol 11;165(6):e Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 6;3: Laan M, Cui ZH, Hoshino H, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 1999;162: Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol 2;169: Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 3;11: Ruddy MJ, Wong GC, Liu XK, et al. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 4;279: Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferongamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol ;115: Homey B, Dieu-Nosjean MC, Wiesenborn A, et al. Up-regulation of macrophage inflammatory protein-3 alpha/ CCL and CC chemokine receptor 6 in psoriasis. J Immunol ;164: Chiricozzi A, Guttman-Yassky E, Suárez-Fariñas M, et al. Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 11;131: Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17a, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 1;2:52ra Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti interleukin-17 receptor antibody for psoriasis. N Engl J Med 12;366: Copyright 12 Massachusetts Medical Society. nejm th anniversary articles The NEJM th Anniversary celebration includes publication of a series of invited review and Perspective articles throughout 12. Each article explores a story of progress in medicine over the past years. The collection of articles is available at the NEJM th Anniversary website, n engl j med 366;13 nejm.org march 29,