Anti–Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis
N Engl J Med 2012; 366:1190-1199March 29, 2012
- 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 hyperproliferation2 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 (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 ixekizumab administered subcutaneously in patients with chronic moderate-to-severe plaque psoriasis.
Study DesignThis double-blind, multicenter, randomized, dose-ranging study was designed to evaluate the safety and efficacy of multiple subcutaneous doses of ixekizumab in patients with chronic moderate-to-severe plaque psoriasis, as defined in the study 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, 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 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 PatientsEligibility 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 assessment (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 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 the study drug. Patients were randomly assigned to receive subcutaneous 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 topical moisturizers or emollients, bath oils, oatmeal bath preparations, or topical salicylic acid preparations for skin conditions during the study, 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 the study unless medically required to treat an adverse event.
End PointsThe 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 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 baseline; the score on the static physician's global assessment, 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 possible 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. Adverse events and routine laboratory values were monitored and evaluated through 20 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 AnalysisAnalyses of baseline characteristics included all randomly assigned patients. Efficacy analyses included patients who received at least one dose of the study 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 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 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 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.
Study PatientsFor the 142 patients, baseline characteristics for the dosing groups were similar (Table 1Table 1Baseline Characteristics of the Patients, According to Study Group.). By 20 weeks, 13 patients (9%) had discontinued treatment; the most common reason for discontinuation (in 4 [3%]) was development of an adverse event (Figure 1Figure 1Enrollment and Follow-up of the Study Patients through 12 Weeks.). Concomitant topical glucocorticoids were used before the primary end point (at 12 weeks) in 1 patient 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.
EfficacyAt 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 2Table 2Study End Points at 12 Weeks, According to Study Group. and Figure 2Figure 2Time 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.). In addition, significantly 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 Figure 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 0 (clear of disease) or of 0 or 1 (minimal disease) (P<0.05 for each dose and score group vs. placebo) (Table 2 and Figure 2; and Figure 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 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 (Figure 2). Among patients with scalp psoriasis, significant 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 Figure 3Figure 3Percent Change in Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) Scores through 20 Weeks, According to Study Group.) 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 (Figure 3). Among patients who reported having psoriatic arthritis, significant reductions from baseline were observed in the 150-mg ixekizumab group at 12 weeks (Table 2), as measured on the joint-pain VAS, and this reduction was sustained through 20 weeks (not shown). Significant reductions in the mean (±SD) DLQI scores were detected at 8 weeks in the 150-mg ixekizumab group (−7.8±5.7), the 75-mg ixekizumab group (−8.5±5.1), and the 25-mg ixekizumab 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 addition, 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).
SafetyThere 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 3Table 3Adverse Events during the Study Period (through 20 Weeks), According to Study Group.). The most common adverse events were nasopharyngitis, 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 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., 1000 to <1500 cells per cubic millimeter) was observed in two patients (receiving either 75 mg or 150 mg of ixekizumab) with no reported symptoms; the lowest neutrophil count observed was 1350 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 150-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 20 weeks. Two patients in the 25-mg ixekizumab group had grade 3 or higher 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.
DiscussionThe 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 moderate-to-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 90% or by 100% as well as in the proportions of patients who had a static physician's global assessment score of 0 or of 0 or 1. These reductions were sustained through 20 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 0 or 1, as compared with placebo, at as early as week 2 in the highest-dose group. Approximately 40% 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 responses compare favorably to responses to other available biologic compounds targeting tumor necrosis 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 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, 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, 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 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 skin-biopsy 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 dermis20,21 and drive angiogenesis.22 In addition, in synergy with tumor necrosis factor α, interleukin-17 causes release of inflammatory cytokines.23-26 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 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 20 weeks with continued treatment. Further studies are needed to establish the long-term safety and efficacy of ixekizumab in the treatment of psoriasis.