Original Article
Brodalumab, an Anti–Interleukin-17–Receptor Antibody for Psoriasis
N Engl J Med 2012; 366:1181-1189March 29, 2012DOI: 10.1056/NEJMoa1109017
- Abstract
Background
In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti–interleukin-17–receptor monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis.
Methods
We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physician's global assessment at week 12.
Results
A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physician's global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%).
Conclusions
Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.)
Media in This Article
Figure 1
Percentage Improvement in PASI Scores over Time.Table 1
Baseline Characteristics of the Patients.Article Activity
- Article
Psoriasis is a chronic T-cell–mediated autoimmune disease1 that affects 2 to 3% of the U.S. population2,3 and 0.6 to 6.5% of the European population.4 Emerging data identify a subset of helper T cells, Th17, that preferentially produce interleukin-17 and play a major role in orchestrating inflammation in psoriasis.5-7 Levels of interleukin-17 are elevated in the lesional skin and blood of patients with psoriasis5,8-10 and correlate with disease severity.11
The interleukin-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE).12 The interleukin 17A, 17F, and 17A/F heterodimer ligands share a common receptor subunit (interleukin-17RA) for signaling.12-14 Levels of interleukin 17A, 17C, and 17F messenger RNA (mRNA) are elevated in the lesional skin of patients with psoriasis,15 and levels of interleukin-17A–positive cells are elevated and localized in psoriatic skin lesions.16 The formation of imiquimod-induced skin lesions resembling psoriasis (accompanied by epidermal expression of interleukins 17A, 17F, and 23) is blocked in mice that are deficient in interleukin-17RA.17 These data suggest that cytokine-targeting strategies aimed at blocking signaling through interleukin-17RA may be beneficial in the treatment of psoriasis.
Brodalumab (AMG 827) is a human, anti–interleukin-17RA monoclonal antibody that antagonizes the interleukin-17 pathway. Brodalumab binds with high affinity to human interleukin-17RA and blocks the biologic activity of interleukins 17A, 17F, 17A/F heterodimer, and 17E (interleukin-25).18,19 Results from a phase 1, proof-of-concept study involving 10 patients with psoriasis showed that a single 700-mg intravenous dose of brodalumab produced substantial improvements in clinical and histopathological variables at 6 weeks. 18,19 The main objective of our study was to establish a dose–response profile for brodalumab and to assess its short-term efficacy and safety in patients with moderate-to-severe plaque psoriasis.
Methods
Patients
Patients 18 to 70 years of age were eligible for the study if they had had stable plaque psoriasis for at least 6 months, had received or were candidates for phototherapy or systemic psoriasis therapy, had a minimum of 10% of their body-surface area affected by psoriasis, and had a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease20,21). Patients were required to have negative test results for hepatitis B virus surface antigen, hepatitis C virus antibody, the human immunodeficiency virus, and tuberculosis (as assessed with the use of a tuberculin skin test) and could not be pregnant or nursing. Each patient provided written informed consent before participating in the study.
Patients with nonplaque or drug-induced psoriasis, a recent serious infection or history of recurrent infections, or a serious concurrent medical illness and patients with an active cancer or a history of cancer, other than in situ cervical or nonmelanoma skin cancers that had been successfully treated, were excluded. Patients who had received systemic therapy, phototherapy, or treatment with biologic agents (other than efalizumab and rituximab) were allowed to participate after specified washout periods. The use of topical therapy during the study was limited to class III to VII glucocorticoids on the scalp, axillae, and groin only; other topical therapies had to be discontinued, and a washout period was required (4 weeks for class I or II glucocorticoids and 2 weeks for all others) before the study drug could be initiated.
Study Design and Oversight
We conducted a randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of brodalumab in patients with moderate-to-severe plaque psoriasis. Patients were randomly assigned to receive placebo or to receive brodalumab, at a dose of 70 mg, 140 mg, or 210 mg, administered subcutaneously on day 1 and at weeks 1, 2, 4, 6, 8, and 10, or at a dose of 280 mg administered subcutaneously on day 1 and at weeks 4 and 8. Patients were enrolled at 23 international sites. Biopsy specimens were obtained from 20 patients before the first dose of study drug was administered and at week 12 for an optional skin-biopsy substudy that was conducted at 7 sites. The study protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board or ethics committee at each participating site. The first patient was enrolled on December 9, 2009, and the enrollment period ended on April 26, 2010.
The study was funded by Amgen. Representatives of Amgen, in collaboration with the first author, designed the study. Amgen conducted the data analyses. All the authors interpreted the data and collaborated in the preparation of the manuscript with support from a professional medical writer funded by Amgen. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol.
Efficacy and Safety Evaluations
The primary efficacy evaluation was the percentage improvement in the PASI score at week 12. Secondary efficacy evaluations included the percentages of patients with a 50%, 75%, 90%, and 100% improvement from baseline in the PASI score; the percentage of body-surface area affected by psoriasis (0 to 100%); and the score on the static physician's global assessment, a 6-point scale with scores ranging from 0 (clear, or no apparent disease) to 5 (severe disease). Patient-reported outcomes included the Dermatology Life Quality Index (DLQI, on which scores range from 0 to 30, with lower scores indicating a lesser effect of the disease on health-related quality of life22) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical and mental summary scores (which range from 0 to 100, with higher scores indicating better well-being23).
Safety was evaluated by assessing adverse events, serious adverse events, and routine hematologic and laboratory values. The National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, was used to grade the severity of adverse events.24 All patients who remained in the study completed an additional visit at week 16 for efficacy and safety assessments.
Statistical Analysis
The analyses of demographic and baseline characteristics and efficacy end points (except patient-reported outcomes) were performed on data from all patients who underwent randomization (full analysis set), according to the intention-to-treat principle. Analyses of safety end points were performed on all patients who underwent randomization and who received at least one dose of a study drug. Patient-reported outcome analyses were performed on data from all patients who underwent randomization and who completed at least one postbaseline assessment. The planned enrollment of 175 patients (about 35 patients in each group) was based on the efficacy end point of 75% improvement in the PASI score; we estimated that with a sample size of 35 in each group, the study would have at least 90% power to detect a difference among the groups in this end point, at a 5% level of significance (two-sided test).
The primary end point (percentage improvement in the PASI score at 12 weeks) was analyzed by means of an analysis of covariance with the use of a linear trend test, with baseline body-mass index and PASI score as the covariates. Under the order-restricted inference, multiple hypotheses concerning all the doses were tested with the use of a closed testing procedure,25 allowing for the assessment of each comparison at the significance level of 0.025 (one-sided) while still maintaining a family-wise false positive rate at 0.025. The t-statistic was used for comparing various dose levels that were based on ordinal scaling.26 All secondary efficacy end points were summarized, and P values were determined. Safety end points were summarized descriptively. Missing data were handled by means of the baseline-value-carried-forward method or the imputation of no response. We graphed the PASI responses from all patients as a cumulative percentage curve by ordering the responses and plotting the results as a percentage of the population.
Results
Patient Characteristics
A total of 188 of the 198 patients who underwent randomization completed the week 16 study evaluation. The numbers of patients, according to study group, who underwent randomization and completed the follow-up and the reasons for discontinuation in the case of patients who did not complete the week 16 evaluation are provided in Figure 1 in the Supplementary Appendix, available at NEJM.org. The baseline demographic and disease characteristics were similar among the five study groups (Table 1Table 1
Baseline Characteristics of the Patients.). In the total cohort, 66% of the patients were men, the mean age was 43 years, the mean duration of psoriasis was 19 years, the mean percentage of body-surface area affected by psoriasis was 24%, and the mean PASI score was 19. The percentage of patients with marked or severe psoriasis, as assessed by means of the static physician's global assessment, was 26% in the placebo group and ranged from 36 to 48% in the various brodalumab groups, although other measures of disease severity at baseline, including PASI score and percentage of body-surface area affected, were generally similar across the groups.Most of the patients had received prior topical treatments (96% of the patients in the combined brodalumab groups and 90% in the placebo group) and prior systemic therapy (78% in the combined brodalumab groups and 71% in the placebo group) (Table 1). The majority of patients (55%) had received prior phototherapy, and 35% of the patients had received prior biologic therapy. Overall, 92% of the patients in the brodalumab groups and 84% in the placebo group received all the planned doses of the study drug. A total of eight patients used concomitant topical glucocorticoids before the week 12 assessment of the primary end point: seven patients (one in the placebo group, one in the 70-mg brodalumab group, one in the 140-mg brodalumab group, two in the 210-mg brodalumab group, and two in the 280-mg brodalumab group) used various formulations of hydrocortisone cream, and one patient in the 210-mg brodalumab group used a disallowed product (betamethasone dipropionate, which is a class II glucocorticoid).
Efficacy
At week 12, the mean percentage improvement in the PASI score was significantly greater in all the brodalumab groups than in the placebo group (P<0.001) (Figure 1Figure 1
Percentage Improvement in PASI Scores over Time.). The mean improvements in the PASI score were significantly greater in the 140-mg brodalumab group, the 210-mg brodalumab group, and the 280-mg brodalumab group than in the 70-mg brodalumab group (85.9%, 86.3%, and 76.0%, respectively, vs. 45.0%; P<0.001); in addition, the mean improvement in the PASI score was significantly greater in each brodalumab group than in the placebo group (16.0%) (P<0.001). The clinical response was rapid, with improvements relative to placebo observed in all brodalumab groups as early as 2 weeks, which was the time of the first postbaseline efficacy measurement (Figure 2 and Figure 3 in the Supplementary Appendix). The mean improvement in the PASI score was similar regardless of whether patients had received prior biologic therapy.The percentages of patients with a 50%, 75%, 90%, or 100% improvement in the PASI score at week 12 were significantly higher among patients who received brodalumab (taking into account all doses) than among patients who received placebo (Table 2Table 2
Clinical Responses at Week 12.). The median percentage improvement in the PASI score was 96.3% in the 140-mg brodalumab group, as compared with 11.8% in the placebo group (Fig. 3 in the Supplementary Appendix). Moreover, about 30% of the patients in the placebo group had worsening psoriasis, as shown by negative values for the percentage improvement in the PASI score (Fig. 3 in the Supplementary Appendix). As was the case with the primary end point, the results for the secondary PASI end points of at least 50% and at least 75% improvement in the PASI score were significant at 2 weeks in all brodalumab groups, and substantial improvement was observed for all secondary PASI end points between week 2 and week 4 (data not shown). Patients who received brodalumab, as compared with placebo, also had a significant decrease in the percentage of body-surface area affected by psoriasis (Table 2). Similarly, a significantly higher percentage of patients in the brodalumab groups than in the placebo group were assessed as being clear of psoriasis (score of 0 on the static physician's global assessment) or as having minimal disease (score of 1) at week 12 (Table 2).Scores on the DLQI were significantly lower (indicating a lesser effect of the disease on health-related quality of life) in the brodalumab groups than in the placebo group (Table 2). The scores on the physical component of the SF-36 were significantly higher (indicating improved well-being) in the 140-mg brodalumab group than in the placebo group, and scores on the SF-36 mental component were significantly higher in the 140-mg and 210-mg brodalumab groups than in the placebo group; the comparisons between the placebo group and the groups receiving the other doses of brodalumab were not significant.
Improvements in skin biomarker measurements were observed in the brodalumab groups (Table 2, and Fig. 4 in the Supplementary Appendix), although the statistical power was limited by the small numbers. Of the 20 pairs of biopsy specimens (obtained before the first dose of study drug was administered and at week 12), 19 could be evaluated by histologic analysis. Keratin 16 (K16) staining of the upper epidermis was reduced in all samples from the 140-mg, 210-mg, and 280-mg groups, with 11 of the 12 samples from these groups having K16 staining confined to the basal keratinocytes at week 12. Epidermal thickness and dermal CD3 counts decreased significantly from baseline in the 140-mg and 210-mg brodalumab groups. Dermal CD3 counts also decreased significantly in the 70-mg brodalumab group, and epidermal thickness decreased significantly in the 280-mg group.
At the week-16 assessment (6 weeks after the last dose of study drug in the 70-mg, 140-mg, and 210-mg brodalumab groups and 8 weeks after the last dose in the 280-mg group), the mean percentage improvements in the PASI score were 40.2%, 72.0%, 75.5%, and 58.5% in the 70-mg, 140-mg, 210-mg, and 280-mg brodalumab groups, respectively, as compared with 13.5% in the placebo group (P<0.001 for the comparison of all brodalumab groups with the placebo group); these improvements were lower than those observed at week 12. Similarly, the percentages of patients with a 50%, 75%, 90%, or 100% improvement in the PASI score at week 16 (data not shown) in all brodalumab groups were lower than the percentages at week 12 (Table 2). A similar trend was observed with respect to the other secondary efficacy end points and with respect to the patient-reported outcomes.
Safety
During the first 12 weeks of the trial, 68% of the patients in the 70-mg brodalumab group, 69% in the 140-mg group, 82% in the 210-mg group, 73% in the 280-mg group, and 62% in the placebo group had at least one adverse event (Table 3Table 3
Adverse Events.). The most commonly reported adverse events were nasopharyngitis, upper respiratory tract infection, arthralgia, and erythema at the injection site (Table 3). The study drug was discontinued in one patient in the 280-mg brodalumab group, who reported mild urticaria on study day 26. Three serious adverse events were reported during the study: renal colic in one patient in the 70-mg brodalumab group on study day 121, which resolved (with no change in the study-drug regimen) on day 134 after hospitalization and surgical intervention; an ectopic pregnancy in one patient in the placebo group on study day 87, which led to hospitalization and surgical intervention but required no change in the study-drug regimen; and grade 3 asymptomatic neutropenia on study day 16 in one patient in the 210-mg brodalumab group. A second case of grade 3 asymptomatic neutropenia was reported on study day 13 in another patient in the 210-mg group. In the case of both patients with neutropenia, the abnormal laboratory values were seen at the first assessment after initiation of the study drug (week 2) and resolved when the study drug was withheld. The second patient restarted the study drug on day 41, after normalization of the absolute neutrophil count, and grade 3 asymptomatic neutropenia developed again 12 days later (study day 53). The study drug was discontinued, and the patient's absolute neutrophil count normalized 17 days later (day 70).
The cumulative incidence of brodalumab binding antibodies (in samples obtained at baseline and at weeks 4, 16, and 22) was similar in all the brodalumab groups: 7.9%, 7.7%, 5.0%, and 9.8% in the 70-mg, 140-mg, 210-mg, and 280-mg groups, respectively. However, no neutralizing antibodies were detected by bioassay.
Discussion
Increased understanding of the immunopathogenesis of psoriasis has led to the development of multiple biologic drugs targeting specific molecules that are essential for the development of psoriatic plaques.27 Overproduction of interleukins 17A, 17F, and 17A/F induces the expression of proinflammatory cytokines with pathologic consequences, including the proliferation of keratinocytes and inflammation of epithelial cells in psoriasis. Therapies targeting this pathway, including interleukin-17 and interleukin-17R, are currently under investigation for the treatment of inflammatory conditions, such as psoriasis and rheumatoid arthritis.19,28-30 Brodalumab, which targets interleukin-17RA, blocks signaling of interleukins 17A and 17F and the interleukin-17A/F heterodimer, all of which play a role in the inflammation of psoriasis.
Findings from this study support interleukin-17RA as a viable target for the treatment of psoriasis. Patients in the 140-mg and 210-mg brodalumab groups had a mean improvement in the PASI score of about 85% at week 12. Brodalumab, as compared with placebo, was associated with a benefit with respect to the outcomes of 50%, 75%, 90%, and 100% improvement in the PASI score; extent of body-surface area affected; score on the static physician's global assessment; score on the DLQI; and skin biomarker measurements. In 11 of 12 biopsy specimens from patients in the three higher-dose brodalumab groups, the histologic and diagnostic features of psoriasis, including T-cell infiltration and suprabasal expression of K16, were no longer seen. This finding indicates a reversal of regenerative epidermal maturation, which is the essential pathological characteristic of psoriasis that causes epidermal hyperplasia and abnormal differentiation, with scaling and thickness as the clinical correlates. Although patients in all the brodalumab groups had significant improvement in efficacy measures as compared with patients in the placebo group, the efficacy results were generally better for patients in the higher-dose groups than for those in the 70-mg group, suggesting that there is a dose–response effect.
Overall, adverse events occurred with greater frequency in the brodalumab groups than in the placebo group. Two cases of grade 3 asymptomatic neutropenia (one of which was a serious adverse event) were reported in the 210-mg brodalumab group. Neutropenia and leukopenia have been observed during treatment with other anti–interleukin-17 biologic therapies (monoclonal antibodies to interleukin-17A) in patients with rheumatoid arthritis.28 The exact mechanism for neutropenia is not known; however, in animal models, interleukin-17 is involved in neutrophil homeostasis through granulocyte colony-stimulating factor, and interleukin-17R–deficient mice have lower levels of neutrophils than do wild-type mice.31,32 This trial was not large enough or of long enough duration to assess the risk of infection or cardiovascular events in the brodalumab groups as compared with the placebo group.
In summary, in this phase 2 study, brodalumab showed a high level of efficacy in patients with moderate-to-severe plaque psoriasis, with a rapid onset of action. These findings also support the important role of interleukin-17RA in the pathogenesis of psoriasis.
Supported by Amgen.
Dr. Papp reports receiving consulting fees from Abbott, Amgen, Astellas, Celgene, Centocor, Eli Lilly, Galderma, Graceway Pharmaceuticals, Janssen, Johnson & Johnson, Merck, Norvartis, Pfizer, and UCB, lecture fees from Abbott, Amgen, Astellas, Celgene, Centocor, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, and Stiefel, and grant support from Abbott, Amgen, Astellas, Celgene, Centocor, Eli Lilly, Galderma, GlaxoSmithKline, Graceway Pharmaceuticals, Janssen, Johnson & Johnson, Medimmune, Merck, Novartis, Pfizer, Stiefel, and UCB; Dr. Leonardi, receiving consulting fees from Abbott, Amgen, Centocor, Eli Lilly, and Pfizer, lecture fees from Abbott and Amgen, and investigator fees from Abbott, Amgen, Celgene, Centocor, Galderma, GlaxoSmithKline, Incyte, Maruho, Novartis, Novo Nordisk, Pfizer, Schering-Plough (now Merck), Sirtris, Stiefel, Vascular Biogenics, and Wyeth (now Pfizer); Dr. Menter, receiving consulting fees from Abbott, Amgen, Astellas, Centocor, Galderma, Genentech, and Wyeth, lecture fees from Abbott, Amgen, Centocor, Galderma, and Wyeth, and fees for expert testimony from Galderma; Dr. Krueger, receiving consulting fees from Centocor, Eli Lilly, and Pfizer and grant support from Amgen, Centocor, Eli Lilly, Merck, and Pfizer; and Drs. Krikorian, Aras, Li, Russell, Thompson, and Baumgartner being full-time employees of Amgen. No other potential conflict of interest was relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Rick Davis, M.S., R.Ph., of Complete Healthcare Communications (whose work was funded by Amgen) and Edward Mancini, D.P.M., and Meera Kodukulla, Ph.D., of Amgen for assistance with the writing of the manuscript; and Ryan Athearn of Amgen for assistance with clinical-trial management.
Source Information
From Probity Medical Research, Waterloo, ON, Canada (K.A.P.); Saint Louis University, St. Louis (C.L.); Baylor University Medical Center, Dallas (A.M.); Hopital de l'Archet, Nice, France (J.-P.O.); Rockefeller University, New York (J.G.K.); Amgen, Thousand Oaks, CA (G.K., G.A., J.L., E.H.Z.T., S.B.); and Amgen, Seattle (C.B.R.).
Address reprint requests to Dr. Papp at Probity Medical Research, 135 Union St., East Waterloo, ON N2J 1C4, Canada, or at kapapp@probitymedical.com.
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Yihua Cai, Chris Fleming, Jun Yan. (2013) Dermal γδ T cells — A new player in the pathogenesis of psoriasis. International Immunopharmacology 16:3, 388-391
2
Jiyeon S. Kim, Martha S. Jordan. (2013) Diversity of IL-17-producing T lymphocytes. Cellular and Molecular Life Sciences 70:13, 2271-2290
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G. R. Tintinger, R. Anderson, C. Feldman. (2013) Pharmacological approaches to regulate neutrophil activity. Seminars in Immunopathology 35:4, 395-409
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Yasmine Belkaid, Shruti Naik. (2013) Compartmentalized and systemic control of tissue immunity by commensals. Nature Immunology 14:7, 646-653
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Wolf-Henning Boehncke, Alan Menter. (2013) Burden of Disease: Psoriasis and Psoriatic Arthritis. American Journal of Clinical Dermatology
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Keven M. Robinson, Michelle L. Manni, Partha S. Biswas, John F. Alcorn. (2013) Clinical Consequences of Targeting IL-17 and TH17 in Autoimmune and Allergic Disorders. Current Allergy and Asthma Reports
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