Psoriasis

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 366;13 nejm.org march 29, 20121190

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.

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 Hos-pital of Copenhagen Gentofte, Hellerup, Denmark (C.Z.); and Lilly Research Labo-ratories, Eli Lilly (G.C., E.E.-H., D.B., S.B.), and Pharmanet/i3 (L.L.) ― both in India-napolis. Address reprint requests to Dr. Leonardi at Central Dermatology PC, 1034 S. Brentwood Blvd., Suite 600, St. Louis, MO 63117, or at leonardi@centralderm .com.

N Engl J Med 2012;366:1190-9.Copyright © 2012 Massachusetts Medical Society.

A BS TR AC T

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 (LY2439821), 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 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 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 90% or by 100%.

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, 10-mg dose) ― 150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%) ― than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both com-parisons). Significant differences occurred at as early as 1 week and were sustained through 20 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 car-diovascular 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, NCT01107457.)

The New England Journal of Medicine Downloaded from nejm.org on October 16, 2012. For personal use only. No other uses without permission.

Copyright © 2012 Massachusetts Medical Society. All rights reserved.

Ixekizumab in Chronic Plaque Psoriasis

n engl j med 366;13 nejm.org march 29, 2012 1191

Psoriasis vulgaris (plaque psoriasis) is a chronic, frequently painful, and often de-bilitating skin disorder. The estimated prev-

alence of diagnosed psoriasis in the United States is 3%, with approximately 17% of these patients hav-ing moderate-to-severe plaque psoriasis.1 Psoriasis is characterized by inflammation and keratinocyte hyperproliferation2 thought to be the pathological consequence of a T-cell–mediated immune re-sponse to an as-yet unidentified autoantigen. Stud-ies 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 pro-inflammatory interleukin-17 cytokine family.4,5 Specific inhibition of interleukin-17A represents a novel, targeted approach to psoriasis treatment.

Ixekizumab (LY2439821) 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 ixeki-zumab administered subcutaneously in patients with chronic moderate-to-severe plaque psoriasis.

Me thods

Study Design

This double-blind, multicenter, randomized, dose-ranging study was designed to evaluate the safety and efficacy of multiple subcutaneous doses of ix-ekizumab in patients with chronic moderate-to-severe plaque psoriasis, as defined in the study pro-tocol (available with the full text of this article at NEJM.org). The protocol was approved by the in-vestigational review board at each site. All patients provided written informed consent. The first pa-tient visit occurred on April 19, 2010; the last, on March 17, 2011. 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 contrib-uted to the interpretation of and vouch for the ac-curacy 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 in-vestigators, 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 0 to 72, with higher scores indicating more severe disease)6 and at least 3 on the static physician’s global assess-ment (on which scores range from 0 [clear of disease] to 5 [severe disease]) at the screening and baseline visits, and psoriasis involving at least 10% of body-surface area at the screening and baseline visits. Exclusion criteria were the presence of non-plaque psoriasis, a clinically significant f lare of psoriasis during the 12 weeks before random-ization, an active infection within 5 days before administration of study drug, a recent serious systemic or local infection requiring hospitaliza-tion 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 concur-rently with the study drug.

Patients were randomly assigned to receive sub-cutaneous injections of placebo or 10 mg, 25 mg, 75 mg, or 150 mg of ixekizumab at 0, 2, 4, 8, 12, and 16 weeks. Patients were permitted to use topi-cal moisturizers or emollients, bath oils, oatmeal bath preparations, or topical salicylic acid prepa-rations for skin conditions during the study, as needed. Other medications could be used as medi-cally 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 approxi-mately 24 hours before visits requiring PASI assessments. No other topical preparations were allowed in the 2 weeks before randomization or during the study unless medically required to treat an adverse event.

End Points

The primary objective was to test whether ixeki-zumab treatment was superior to placebo, as mea-sured 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 percent-age of reduction in the PASI score in each treat-ment group, by means of regression techniques. The PASI score combines assessments of the extent





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 0 for no psoriasis to 72 for the worst possible psoriasis.6

Secondary end points included reduction in the PASI score by at least 90% or by 100% over base-line; the score on the static physician’s global as-sessment, which is used to grade psoriasis lesions at a given time point (with 0 for clear of disease and 5 for severe disease); the joint-pain visual-analogue scale (VAS), which assesses joint pain from psoriatic arthritis reported by the patient (score range, 0 [no pain] to 100 [severe pain]); the Nail Psoriasis Severity Index (NAPSI), which scores the nail matrix and nail bed of each finger and toe (score range, 0 [no nail psoriasis] to 160 [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, 0 [no psoriasis] to 72 [worst pos-sible scalp psoriasis]). These end points were ascertained at baseline and at 1, 2, 4, 6, 8, 12, 16, and 20 weeks.

Two additional secondary end points (both patient-reported) were collected only at weeks 0, 8, and 16: an itch VAS (on which scores range from 0 [no itching] to 100 [severe itching]) and the Dermatology Life Quality Index (DLQI, on which scores ranging from 0 to 30, 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. Ad-verse events and routine laboratory values were monitored and evaluated through 20 weeks. Ad-verse events of special interest included allergic reactions or hypersensitivities, injection-site reac-tions, and infections. Laboratory abnormalities of special interest included cytopenias (leukopenia, neutropenia, and thrombocytopenia) and liver biochemical-test elevations (of alanine aminotrans-ferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase).

Statistical Analysis

Analyses of baseline characteristics included all randomly assigned patients. Efficacy analyses in-cluded patients who received at least one dose of the study drug and had at least one postbaseline

efficacy assessment. Safety analyses were con-ducted 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 avail-able 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 non-response at that time point.

For the primary analysis, we expected to ob-serve a reduction in the PASI score by at least 75% over a 12-week period in at least 70% of patients receiving the optimal ixekizumab dose and in 10% of patients receiving placebo. On this basis, we estimated that pairwise comparison of an ixeki-zumab group and the placebo group would have more than 99% power, with the use of a two-sided Fisher’s exact test at the 0.05 significance level. The rates of reduction in the PASI score by at least 75% or 90% or by 100% 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 20 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 pa-tient in the 150-mg ixekizumab group, who used desoximetasone ointment from 8 to 10 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 90% occurred in significantly more patients in the 25-mg, 75-mg, and 150-mg ixekizumab groups (P<0.001 for each vs. placebo) (Table 2 and Fig. 2). In addition, sig-





nificantly more patients in the 75-mg and 150-mg groups had a reduction in the PASI score by 100% (complete skin clearance) (P<0.001 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 percent-ages of patients in the three highest ixekizumab dose groups had a static physician’s global assess-ment score of 0 (clear of disease) or of 0 or 1 (mini-mal disease) (P<0.05 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 signifi-cant differences between the 150-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 0 or 1.

Differences with the placebo group were sustained through 20 weeks for all clinical measures (Fig. 2).

Among patients with scalp psoriasis, signifi-cant reductions in the PSSI score were observed in the 25-mg, 75-mg, and 150-mg ixekizumab groups versus placebo at 12 weeks (Table 2 and Fig. 3) and were sustained through 20 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 20 weeks (Fig. 3). Among patients who reported having psoriatic arthritis, significant reductions from baseline were observed in the 150-mg ixekizu-mab group at 12 weeks (Table 2), as measured on the joint-pain VAS, and this reduction was sus-tained through 20 weeks (not shown).

Significant reductions in the mean (±SD) DLQI scores were detected at 8 weeks in the 150-mg ix-ekizumab group (−7.8±5.7), the 75-mg ixekizu-mab group (−8.5±5.1), and the 25-mg ixekizu-

Table 1. Baseline Characteristics of the Patients, According to Study Group.*

CharacteristicPlacebo (N = 27) Ixekizumab P Value†

10 mg (N = 28)

25 mg (N = 30)

75 mg (N = 29)

150 mg (N = 28)

Age ― yr 45±13 48±11 46±15 46±13 46±13 0.96

Male sex ― no. (%) 14 (52) 16 (57) 18 (60) 19 (66) 14 (50) 0.77

Weight ― kg 92±23 95±28 97±26 95±27 88±24 0.68

Duration of psoriasis ― yr 15±11 21±12 18±11 13±10 15±10 0.08

Previous systemic therapy ― no. (%) 13 (48) 12 (43) 9 (30) 6 (21) 10 (36) 0.22

Body-surface area ― % 19±12 22±18 22±12 21±11 21±13 0.83

PASI score‡ 16.5±5.3 19.2±8.0 18.6±4.9 17.2±4.3 17.7±6.2 0.44

sPGA score§ 3.3±0.6 3.3±0.5 3.4±0.5 3.2±0.5 3.3±0.4 0.84

PSSI score¶ 19.6±14.2 19.5±14.6 20.5±13.7 13.8±8.7 19.4±12.0 0.51

NAPSI score‖ 35.0±28.1 41.9±44.8 34.9±37.7 45.0±46.9 46.5±51.7 0.93

DLQI score** 11.4±5.9 10.6±7.2 11.6±7.2 11.1±5.6 10.4±5.8 0.94

* 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 0 to 72, with higher scores indicating more severe

disease.§ Scores on the static physician’s global assessment (sPGA) range from 0 (clear of disease) to 5 (severe disease).¶ Scores on Psoriasis Scalp Severity Index (PSSI) range from 0 (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 10-mg group, 24 of the 30 patients in the 25-mg group, 18 of the 29 patients in the 75-mg group, and 22 of the 28 patients in the 150-mg group.

‖ Scores on the Nail Psoriasis Severity Index (NAPSI) range from 0 (no nail psoriasis) to 160 (worst possible nail psori-asis). 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 10-mg group, 10 of the 30 patients in the 25-mg group, 10 of the 29 patients in the 75-mg group, and 10 of the 28 patients in the 150-mg group.

** Scores on the Dermatology Life Quality Index (DLQI) range from 0 to 30, with higher scores indicating worse health-related quality of life.





mab group (−7.1±6.5) as compared with placebo (−2.4±4.4) (P<0.001 for all comparisons). These significant reductions were sustained through 16 weeks (P<0.001 for all comparisons). In addi-tion, at 16 weeks, significantly more patients had a DLQI score of 0 in the 150-mg, 75-mg, and 25-mg ixekizumab groups (39.3%, 37.9%, and 31.0%, respectively) as compared with placebo (0%, P<0.05 for all comparisons). The 25-mg, 75-mg, and 150-mg treatment groups also had significant reductions in itch severity (VAS scores) as compared with the placebo group from 8 through 16 weeks (P<0.001) (data not shown).

Safety

There were no reported serious adverse events, in-cluding 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 naso-pharyngitis, upper respiratory infection, injection-site reaction, and headache. A total of four patients discontinued the study because of the following adverse events: hypertriglyceridemia (one patient receiving placebo), peripheral edema (one patient receiving 10 mg of ixekizumab), hypersensitivity (one patient receiving 10 mg of ixekizumab), and urticaria (one patient receiving 25 mg of ixekizu-mab). Across all four ixekizumab groups, six pa-tients reported injection-site reactions; none were

severe, and no patients discontinued treatment because of these reactions. There were no instanc-es of anaphylactic reaction, angioedema, or major cardiovascular events (e.g., cardiovascular death, nonfatal myocardial infarction, or stroke). No se-rious infections, including mycobacterial or sys-temic fungal infections, were reported. There were no significant changes in mean absolute neutrophil counts with ixekizumab treatment. Neutropenia with a Common Terminology Crite-ria for Adverse Events (CTCAE)9 grade of 2 (i.e., 1000 to <1500 cells per cubic millimeter) was ob-served in two patients (receiving either 75 mg or 150 mg of ixekizumab) with no reported symp-toms; the lowest neutrophil count observed was 1350 per cubic millimeter (Table 1 in the Supple-mentary Appendix). No obvious dose-related trend in infections or other adverse events was ob-served. In one patient in the ixekizumab 150-mg group with a history of treated basal-cell carci-noma, two new basal-cell carcinomas were detect-ed during the treatment period. No other cancer was reported.

Mean values for the serum transaminases ala-nine aminotransferase and aspartate aminotrans-ferase and total and direct bilirubin showed no significant changes from baseline in any ixekizu-mab group, as compared with the placebo group, from 1 through 20 weeks. Two patients in the 25-mg ixekizumab group had grade 3 or higher

142 Patients were enrolled andunderwent randomization

27 Were assigned toreceive placebo

4 Discontinuedthe study

1 Had adverseevent

1 Withdrew2 Had lack of

efficacy

23 Completed the study

28 Were assigned toreceive subcutaneous

ixekizumab, 10 mg

6 Discontinuedthe study

2 Had adverseevents

2 Had protocolviolations

1 Was lost tofollow-up

1 Had lack ofefficacy



ixekizumab, 25 mg

1 Discontinuedthe study owingto adverse event



ixekizumab, 75 mg

1 Discontinuedthe study owing topatient withdrawal


28 Were assigned toreceive subcutaneousixekizumab, 150 mg

1 Discontinuedthe study owing topatient withdrawal


Figure 1. Enrollment and Follow-up of the Study Patients through 12 Weeks.





elevations of creatine kinase and aspartate ami-notransferase (one also had a grade 3 elevation of alanine aminotransferase) that increased from the time of the screening visit or baseline without as-sociated symptoms. These elevated enzyme levels decreased over time, and both patients continued ixekizumab treatment, while total and direct bili-rubin and alkaline phosphatase levels remained normal throughout.

Discussion

The results of this study demonstrate that neu-tralization of interleukin-17 with the humanized monoclonal antibody ixekizumab may be an effec-tive treatment for patients with chronic moderate-to-severe plaque psoriasis. At 12 weeks, significant and dose-dependent increases were seen in the pro-

portions of patients receiving ixekizumab who had a reduction in the PASI score by at least 75% or 90% or by 100% as well as in the proportions of patients who had a static physician’s global as-sessment score of 0 or of 0 or 1. These reductions were sustained through 20 weeks. Consistent with these clinical improvements, DLQI scores and itch-ing severity also significantly decreased with ix-ekizumab treatment.

Ixekizumab had a rapid onset of action, as evi-denced 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 0 or 1, as compared with placebo, at as early as week 2 in the highest-dose group. Approximately 40%

Table 2. Study End Points at 12 Weeks, According to Study Group.*

VariablePlacebo

(N = 26)† Ixekizumab

10 mg (N = 28)

25 mg (N = 30)

75 mg (N = 29)

150 mg (N = 28)

PASI score 13.5±7.5 10.2±10.0‡ 4.5±6.2‡ 2.5±3.7‡ 2.4±4.2‡

Reduction in PASI score — no. (%)

By ≥75% 2 (8) 8 (29) 23 (77)‡ 24 (83)‡ 23 (82)‡

By ≥90% 0 5 (18) 15 (50)‡ 17 (59)‡ 20 (71)‡

By 100% 0 0 5 (17) 11 (38)‡ 11 (39)‡

sPGA score — no. (%)

0 or 1 2 (8) 7 (25) 21 (70)‡ 21 (72)‡ 20 (71)‡

0 0 2 (7) 6 (20)§ 11 (38)‡ 13 (46)‡

NAPSI — % change from baseline¶ 6.8±41.1 14.3±97.8 −24.0±32.8 –57.1±36.7‖ −49.3±35.9§

PSSI — % change from baseline** −30.5±95.5 −43.4±62.8 −87.1±23.6‡ −94.8±14.5‡ −84.8±41.5‖

Joint-pain VAS score — change from baseline†† 4.8±48.2 −5.9±47.6 −17.0±28.1 −18.6±13.4 −39.0±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 co-variance 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≤0.001 versus placebo.§ P<0.05 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

10-mg group, 10 of the 30 patients in the 25-mg group, 10 of the 29 patients in the 75-mg group, and 10 of the 28 patients in the 150-mg group.

‖ P≤0.01 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 10-mg group, 24 of the 30 patients in the 25-mg group, 18 of the 29 patients in the 75-mg group, and 22 of the 28 patients in the 150-mg group.

†† Scores on the joint-pain VAS range from 0 (no pain) to 100 (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 10-mg group, 11 of the 30 patients in the 25-mg group, 8 of the 29 patients in the 75-mg group, and 8 of the 28 patients in the 150-mg group. The baseline means were 37.0±28.5 in the pla-cebo group, 40.4±30.0 in the 10-mg group, 34.9±32.1 in the 25-mg group, 35.2±19.4 in the 75-mg group, and 45.0±27.4 in the 150-mg group.





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 100% or a static physician’s global assessment score of 0 at 12 weeks. Although it is difficult to draw conclusions from cross-study comparisons, the magnitude and rapidity of the clinical re-sponses compare favorably to responses to other available biologic compounds targeting tumor ne-crosis factor, T cells, or interleukin-12/23 p40.10‑13 Although interleukin-23 can drive the maturation of type 17 helper T cells,2 interleukin-17 and inter-leukin-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. Improve-ments 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 ac-cording to the NAPSI, both fingernails and toe-nails were included. Because toenails grow more slowly than fingernails, a longer treatment dura-tion than that used in this trial may be required to assess greater effects of the treatment on toe-nails.17

No serious adverse events, including deaths,

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150-mg ixekizumab(N=28)


Placebo(N=26)



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 20 Weeks, 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 90% (Panel B), and 100% (Panel C), respectively. Panel D shows the percentage of patients who had an sPGA score of 0 (clear of disease) or 1 (minimal disease). Asterisks indicate significant differences (P<0.05) 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).





were observed in any group. Our study was not large enough or of long enough duration to as-certain uncommon adverse events. Although infec-tions 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 subcutane-ous 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 discontinua-tion. Two patients in the 25-mg ixekizumab group had grade 3 or greater elevations in creatine ki-nase, aspartate aminotransferase, or alanine ami-notransferase levels that returned to screening or baseline levels over time with continued ixekizu-mab treatment. No major cardiovascular events, mycobacterial infections, or systemic fungal infec-tions 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, 1350 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 mobi-lization and homeostasis,14 it is not clear whether there is an association between interleukin-17 inhi-bition and neutropenia in psoriasis.

In a previous proof-of-concept study of ixekizu-

mab 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 skin-biopsy specimens, including reductions in acan-thosis, keratinocyte proliferation, and dermal infil-tration of lymphocytes and other inflammatory cells within 2 weeks.18 These changes were ac-companied 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 ixekizu-mab 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 dermis20,21 and drive angiogenesis.22 In ad-dition, in synergy with tumor necrosis factor α, interleukin-17 causes release of inflammatory cyto-kines.23‑26 Furthermore, in a trial exploring the efficacy of another investigational monoclonal antibody (AIN457) against interleukin-17, reduc-tions 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

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Weeks

B PSSI Score

150-mg ixekizumab (N=10)


Placebo (N=16)10-mg ixekizumab (N=13)




Placebo (N=20)10-mg ixekizumab (N=21)


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Figure 3. Percent Change in Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) Scores through 20 Weeks, 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<0.05) between each study group and placebo.





Taken together, these data suggest that inhibi-tion of interleukin-17 may be an effective and tar-geted therapy for psoriasis. Patients with chronic moderate-to-severe plaque psoriasis treated with ixekizumab had significant improvement in clini-cal measures during the 12-week treatment period that were rapid and sustained through 20 weeks with continued treatment. Further studies are

needed to establish the long-term safety and effi-cacy 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 the study de-

sign; 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.

Table 3. Adverse Events during the Study Period (through 20 Weeks), According to Study Group.*

VariablePlacebo (N = 27) Ixekizumab

10 mg (N = 28)

25 mg (N = 30)

75 mg (N = 29)

150 mg (N = 28)

No. of adverse events 40 52 42 46 35

No. of serious adverse events 0 0 0 0 0

≥1 Adverse event — no. of patients (%) 17 (63) 21 (75) 21 (70) 17 (59) 13 (46)

Adverse events — no. of patients (%)

Infection or infestation 7 (26) 12 (43) 9 (30) 9 (31) 8 (29)

Nasopharyngitis 5 (19) 3 (11) 3 (10) 3 (10) 4 (14)

Upper respiratory infection 1 (4) 1 (4) 3 (10) 1 (3) 1 (4)

Injection-site reaction 0 0 3 (10) 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 in-clude 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.

References

1. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol 2009;60:218-24. [Erratum, J Am Acad Dermatol 2009;61:507.]2. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoria-sis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 2007;9: 461-7.3. Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inf lammation. Curr Opin Immunol 2006;18:670-5. [Erratum, Curr Opin Immunol 2007;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 pa-tients with active psoriasis and correlation with disease severity. Mediators Inflamm 2005;2005:273-9.5. Li J, Chen X, Liu Z, Yue Q, Liu H. Ex-pression of Th17 cytokines in skin lesions

of patients with psoriasis. J Huazhong Univ Sci Technolog Med Sci 2007;27:330-2.6. Fredriksson T, Pettersson U. Severe psoriasis — oral therapy with a new reti-noid. Dermatologica 1978;157:238-44.7. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) — a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-6.8. Kimball AB, Krueger GG, Woolley JM. Minimal important differences for the der-matology life quality index (DLQI) in pso-riasis patients. Presented at the meeting of the American Academy of Dermatology, New York, July 28–August 1, 2004. (Poster.)9. Common Terminology Criteria for Ad-verse Events (CTCAE), version 3.0. August 9, 2006 (http://ctep.cancer.gov/protocol Development/electronic_applications/docs/ctcaev3.pdf).10. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in pa-tients with psoriasis. N Engl J Med 2003; 349:2014-22.

11. 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, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371:1665-74. [Erratum, Lancet 2008;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, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008;371:1675-84.13. Reich K, Nestle FO, Papp K, et al. Inflix-imab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 2005;366:1367-74.14. Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Im-munity 2004;21:467-76.15. Tyring S, Mendoza N, Appell M, et al.





A calcipotriene/betamethasone dipropio-nate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American pa-tients: results of the randomized, 8-week, double-blind phase of a clinical trial. Int J Dermatol 2010;49:1328-33.16. van de Kerkhof PC, Franssen ME. Pso-riasis of the scalp: diagnosis and manage-ment. Am J Clin Dermatol 2001;2:159-65.17. Rigopoulos D, Gregoriou S, Lazaridou E, et al. Treatment of nail psoriasis with adalimumab: an open label unblinded study. J Eur Acad Dermatol Venereol 2010; 24:530-4.18. Krueger J, Fretzin S, Farinas M, et al. Interleukin-17A is an essential cytokine to sustain pathogenic cell activation and in-flammatory gene circuits in psoriasis vul-garis. Br J Dermatol 2011;165(6):e6.19. Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyper-plasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis

pathogenesis. J Exp Med 2006;203:2577-87.20. Laan M, Cui ZH, Hoshino H, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the air-ways. J Immunol 1999;162:2347-52.21. Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimu-lates cytokine production and inhibits hemopoiesis. J Immunol 2002;169:642-6.22. Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003;101:2620-7.23. Ruddy MJ, Wong GC, Liu XK, et al. Functional cooperation between interleu-kin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 2004;279:2559-67.24. Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Inter-leukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-

gamma- and interleukin-4-induced acti-vation of human keratinocytes. J Invest Dermatol 2000;115:81-7.25. Homey B, Dieu-Nosjean MC, Wiesen-born A, et al. Up-regulation of macro-phage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis. J Immunol 2000;164:6621-32.26. Chiricozzi A, Guttman-Yassky E, Suárez-Fariñas M, et al. Integrative re-sponses to IL-17 and TNF-α in human keratinocytes account for key inflamma-tory pathogenic circuits in psoriasis. J Invest Dermatol 2011;131:677-87.27. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheuma-toid arthritis, and uveitis. Sci Transl Med 2010;2:52ra72.28. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti–interleukin-17–recep-tor antibody for psoriasis. N Engl J Med 2012;366:1181-9.Copyright © 2012 Massachusetts Medical Society.

nejm 200th anniversary articles

The NEJM 200th Anniversary celebration includes publication of a series of invited review and Perspective articles throughout 2012.

Each article explores a story of progress in medicine over the past 200 years. The collection of articles is available at the NEJM 200th Anniversary website,

http://NEJM200.NEJM.org.



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