Brodalumab, An Anti–Interleukin-17–Receptor Antibody for Psoriasis

8/17/2019 Brodalumab, An Anti–Interleukin-17–Receptor Antibody for Psoriasis

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n engl j med 366;13 nejm.org march 29 , 2012 1181

The new englandjournal of medicineestablished in 1812 march 29, 2012 vol. 366 no. 13

Brodalumab, an Anti–Interleukin-17–Receptor Antibodyfor Psoriasis

Kim A. Papp, M.D., Ph.D., Craig Leonardi, M.D., Alan Menter, M.D., Jean-Paul Ortonne, M.D., James G. Krueger, M.D., Gregory Kricorian, M.D., Girish Aras, Ph.D., Juan Li, Ph.D., Chris B. Russell, Ph.D.,

Elizabeth H.Z. Thompson, Ph.D., and Scott Baumgartner, M.D.

A b s t r a c t

From Probity Medical Research, Waterloo,ON, Canada (K.A.P.); Saint Louis Univer-sity, St. Louis (C.L.); Baylor UniversityMedical Center, Dallas (A.M.); Hopital del’Archet, Nice, France (J.-P.O.); RockefellerUniversity, 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 atProbity Medical Research, 135 Union St.,East Waterloo, ON N2J 1C4, Canada, orat [email protected].

N Engl J Med 2012;366:1181-9.Copyright © 2012 Massachusetts Medical Society.

Background

In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the eff icacy 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 indicat-ing more severe disease) and with 10% or more of their body-surface area affectedby psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was thepercentage improvement from baseline in the PASI score at week 12. Secondary endpoints included improvement of at least 75% and at least 90% in the PASI score andthe score on the static physician’s global assessment at week 12.

Results

A total of 198 patients underwent randomization. At week 12, the mean percentageimprovements in the PASI score were 45.0% among patients receiving 70 mg ofbrodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receivingplacebo (P


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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 366;13 nejm.org march 29 , 20121182

Psoriasis is a chronic T-cell–mediated autoimmune disease 1 that affects 2 to 3% ofthe U.S. population 2,3 and 0.6 to 6.5% of theEuropean population. 4 Emerging data identify asubset of helper T cells, Th17, that preferentiallyproduce interleukin-17 and play a major role inorchestrating inflammation in psoriasis. 5-7 Levelsof interleukin-17 are elevated in the lesional skinand blood of patients with psoriasis 5,8-10 and cor-relate with disease severity. 11

The interleukin-17 cytokine family consists ofsix cytokines (interleukins 17A to 17F) and fivereceptors (interleukins 17RA to 17RE). 12 The in-terleukin 17A, 17F, and 17A/F heterodimer ligandsshare a common receptor subunit (interleukin-17RA) for signaling. 12-14 Levels of interleukin 17A,17C, and 17F messenger RNA (mRNA) are elevat-ed in the lesional skin of patients with psoriasis, 15 and levels of interleukin-17A–positive cells are el-evated and localized in psoriatic skin lesions. 16 Theformation of imiquimod-induced skin lesionsresembling psoriasis (accompanied by epidermalexpression of interleukins 17A, 17F, and 23) isblocked in mice that are deficient in interleukin-17RA.17 These data suggest that cytokine-targetingstrategies aimed at blocking signaling throughinterleukin-17RA may be beneficial in the treat-ment of psoriasis.

Brodalumab (AMG 827) is a human, anti–inter-leukin-17RA monoclonal antibody that antagoniz-es the interleukin-17 pathway. Brodalumab binds

with high affinity to human interleukin-17RA andblocks 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 in-

volving 10 patients with psoriasis showed that asingle 700-mg intravenous dose of brodalumabproduced substantial improvements in clinical andhistopathological variables at 6 weeks. 18,19 Themain objective of our study was to establish adose–response profile for brodalumab and to as-sess its short-term eff icacy and safety in patients

with moderate-to-severe plaque psoriasis.

Methods

Patients

Patients 18 to 70 years of age were eligible for thestudy if they had had stable plaque psoriasis for atleast 6 months, had received or were candidates forphototherapy or systemic psoriasis therapy, had aminimum of 10% of their body-surface area af-

fected by psoriasis, and had a score of 12 or higheron the psoriasis area-and-severity index (PASI, on

which scores range from 0 to 72, with higher scoresindicating more severe disease 20,21 ). Patients wererequired to have negative test results for hepatitis B

virus surface antigen, hepatitis C virus antibody,the human immunodeficiency virus, and tubercu-losis (as assessed with the use of a tuberculin skintest) and could not be pregnant or nursing. Eachpatient provided written informed consent beforeparticipating in the study.

Patients with nonplaque or drug-induced pso-riasis, a recent serious infection or history of re-current infections, or a serious concurrent medicalillness and patients with an active cancer or a his-tory of cancer, other than in situ cervical or non-melanoma skin cancers that had been success-fully treated, were excluded. Patients who hadreceived systemic therapy, phototherapy, or treat-ment with biologic agents (other than efalizumaband rituximab) were allowed to participate afterspecified washout periods. The use of topicaltherapy during the study was limited to class III toVII glucocorticoids on the scalp, axillae, and groinonly; other topical therapies had to be discontin-ued, and a washout period was required (4 weeksfor class I or II glucocorticoids and 2 weeks for allothers) before the study drug could be initiated.

Study Design and Oversight

We conducted a randomized, double-blind, place-bo-controlled, dose-ranging study to evaluate theeff icacy and safety of brodalumab in patients withmoderate-to-severe plaque psoriasis. Patients wererandomly assigned to receive placebo or to re-ceive brodalumab, at a dose of 70 mg, 140 mg, or210 mg, administered subcutaneously on day 1 andat weeks 1, 2, 4, 6, 8, and 10, or at a dose of 280 mgadministered subcutaneously on day 1 and at weeks4 and 8. Patients were enrolled at 23 internationalsites. Biopsy specimens were obtained from 20 pa-tients before the first dose of study drug was ad-

ministered and at week 12 for an optional skin-biopsy substudy that was conducted at 7 sites. Thestudy protocol (available with the full text of thisarticle at NEJM.org) was approved by the institu-tional review board or ethics committee at eachparticipating site. The first patient was enrolledon December 9, 2009, and the enrollment periodended on April 26, 2010.

The study was funded by Amgen. Representa-tives of Amgen, in collaboration with the first

The New England Journal of MedicineDownloaded from nejm.org on May 18, 2016. For personal use only. No other uses without permission.

Copyright © 2012 Massachusetts Medical Society. All rights reserved.


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Brodalumab for Psoriasis


author, designed the study. Amgen conducted thedata analyses. All the authors interpreted the dataand collaborated in the preparation of the man-uscript with support from a professional medical

writer funded by Amgen. All the authors made thedecision to submit the manuscript for publicationand vouch for the completeness and accuracy ofthe data and analyses and for the fidelity of thestudy to the protocol.

Efficacy and Safety Evaluations

The primary eff icacy evaluation was the percentageimprovement in the PASI score at week 12. Second-ary efficacy evaluations included the percentages ofpatients with a 50%, 75%, 90%, and 100% im-provement from baseline in the PASI score; the per-centage of body-surface area affected by psoriasis(0 to 100%); and the score on the static physician’sglobal assessment, a 6-point scale with scores rang-ing from 0 (clear, or no apparent disease) to 5 (se-

vere disease). Patient-reported outcomes includedthe Dermatology Life Quality Index (DLQI, on

which scores range from 0 to 30, with lower scoresindicating a lesser effect of the disease on health-related quality of life 22 ) and the Medical OutcomesStudy 36-Item Short-Form Health Survey (SF-36)physical and mental summary scores (which rangefrom 0 to 100, with higher scores indicating better

well-being 23 ).Safety was evaluated by assessing adverse

events, serious adverse events, and routine hema-tologic and laboratory values. The National CancerInstitute’s Common Terminology Criteria for Ad-

verse Events, version 4.0, was used to grade theseverity of adverse events. 24 All patients who re-mained in the study completed an additional visitat week 16 for efficacy and safety assessments.

Statistical Analysis

The analyses of demographic and baseline charac-teristics and efficacy end points (except patient-reported outcomes) were performed on data from

all patients who underwent randomization (fullanalysis set), according to the intention-to-treatprinciple. Analyses of safety end points were per-formed on all patients who underwent randomiza-tion and who received at least one dose of a studydrug. Patient-reported outcome analyses were per-formed on data from all patients who underwentrandomization and who completed at least onepostbaseline assessment. The planned enrollmentof 175 patients (about 35 patients in each group)

was based on the eff icacy end point of 75% im-provement 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 differ-ence among the groups in this end point, at a 5%level of signif icance (two-sided test).

The primary end point (percentage improve-ment in the PASI score at 12 weeks) was analyzedby means of an analysis of covariance with the useof a linear trend test, with baseline body-massindex and PASI score as the covariates. Under theorder-restricted inference, multiple hypothesesconcerning all the doses were tested with theuse of a closed testing procedure, 25 allowing forthe assessment of each comparison at the signifi-cance level of 0.025 (one-sided) while still main-taining a family-wise false positive rate at 0.025.The t-statistic was used for comparing various doselevels that were based on ordinal scaling. 26 Allsecondary efficacy end points were summarized,and P values were determined. Safety end points

were summarized descriptively. Missing data werehandled by means of the baseline-value-carried-forward method or the imputation of no response.We graphed the PASI responses from all patientsas a cumulative percentage curve by ordering theresponses and plotting the results as a percent-age of the population.

R e s u l t s

Patient Characteristics

A total of 188 of the 198 patients who underwentrandomization completed the week 16 study eval-uation. The numbers of patients, according to studygroup, who underwent randomization and com-pleted the follow-up and the reasons for discontin-uation in the case of patients who did not completethe week 16 evaluation are provided in Figure 1 inthe Supplementary Appendix, available at NEJM.org. The baseline demographic and disease char-acteristics were similar among the five study groups

(Table 1 ). In the total cohort, 66% of the patients were men, the mean age was 43 years, the meanduration of psoriasis was 19 years, the mean per-centage of body-surface area affected by psoriasis

was 24%, and the mean PASI score was 19. Thepercentage of patients with marked or severe pso-riasis, as assessed by means of the static physi-cian’s global assessment, was 26% in the placebogroup and ranged from 36 to 48% in the variousbrodalumab groups, although other measures of




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Table 1. Baseline Characteristics of the Patients.*

VariablePlaceboN = 38) Brodalumab†

70 mg(N = 39)

140 mg(N = 39)

210 mg(N = 40)

280 mg(N = 42)

Total(N = 160)

Age — yr 41.8±14.4 42.1±11.1 44.0±11.7 42.1±12.2 42.3±12.2 42.6±11.7

Male sex — no. (%) 22 (58) 22 (56) 28 (72) 25 (62) 30 (71) 105 (66)White race — no. (%)‡ 32 (84) 36 (92) 37 (95) 34 (85) 36 (86) 143 (89)

Weight — kg 86.9±20.6 88.8±22.0 92.4±23.7 90.4±20.4 91.5±22.9 90.8±22.1

Body-mass index§ 29.3±6.8 30.3±7.1 30.8±7.0 29.8±6.6 31.0±6.3 30.5±6.7

Duration of psoriasis — yr 18.3±11.5 20.7±11.8 19.2±9.7 17.1±10.1 19.3±12.4 19.1±11.0

Psoriatic arthritis — no. (%)¶ 7 (18) 8 (21) 11 (28) 12 (30) 8 (19) 39 (24)

Percentage of body-surface area affected 23.5±12.8 24.1±12.8 24.9±16.9 25.0±15.5 21.3±11.0 23.8±14.1

PASI score∥ 18.9±5.9 18.8±5.7 19.4±8.0 20.6±7.8 17.9±5.5 19.2±6.8

Marked or severe psoriasis on the basis of thestatic physician’s global assessment —no. (%)**

10 (26) 14 (36) 16 (41) 19 (48) 15 (36) 64 (40)

Prior topical treatment — no. (%) 34 (89) 37 (95) 39 (100) 37 (92) 40 (95) 153 (96)Prior phototherapy — no. (%)

PUVA 7 (18) 9 (23) 8 (21) 8 (20) 10 (24) 35 (22)

UVB 17 (45) 18 (46) 12 (31) 15 (38) 24 (57) 69 (43)

Prior systemic therapy — no. (%) 27 (71) 31 (79) 25 (64) 32 (80) 36 (86) 124 (78)

Nonbiologic therapy

Methotrexate 9 (24) 19 (49) 16 (41) 16 (40) 17 (40) 68 (42)

Oral or intramuscular glucocorticoids 5 (13) 4 (10) 3 (8) 4 (10) 5 (12) 16 (10)

Cyclosporine 3 (8) 3 (8) 4 (10) 4 (10) 6 (14) 17 (11)

Oral retinoids 2 (5) 2 (5) 6 (15) 7 (18) 6 (14) 21 (13)

Biologic therapyEtanercept 7 (18) 7 (18) 3 (8) 4 (10) 7 (17) 21 (13)

Adalimumab 4 (11) 3 (8) 5 (13) 7 (18) 8 (19) 23 (14)

Ustekinumab 5 (13) 6 (15) 2 (5) 6 (15) 4 (10) 18 (11)

DLQI score†† 13.3±7.0 12.4±7.2 11.1±6.7 11.4±6.4 10.8±6.6 11.4±6.7

SF-36 score‡‡

Physical component 48.6±9.8 50.2±9.4 50.6±8.2 48.1±8.9 50.1±8.5 49.7±8.7

Mental component 45.2±14.5 45.4±12.8 47.5±12.8 48.7±12.6 45.6±11.4 46.8±12.3

* Plus–minus values are means ±SD. There were no significant differences among the groups with respect to baseline characteristics. PUVAdenotes psoralen and ultraviolet A, and UVB ultraviolet B.

† The 70-, 140-, and 210-mg doses of brodalumab were administered on day 1 and at weeks 1, 2, 4, 6, 8, and 10; the 280-mg dose was ad-ministered once a month.

‡ Race was self-reported.§ The body-mass index is the weight in kilograms divided by the square of the height in meters.¶ Patients were included if a diagnosis of psoriatic arthritis was reported in a disease-specific medical history.∥ The psoriasis area-and-severity index (PASI) score (which ranges from 0 to 72, with higher scores indicating more severe disease) is based

on the extent of involvement and the degree of erythema, scaling, and induration of psoriatic plaques in four separate body areas (head,trunk, arms, and legs).

** The static physician’s global assessment (a 6-point scale, with 0 indicating clear of disease and 5 indicating severe disease) is an assess-ment by the physician of the patient’s psoriasis on the basis of the severity of erythema, scaling, and induration.

†† The Dermatology Life Quality Index (DLQI) is a skin-disease–specific instrument that is scored on a scale from 0 to 30, with higher scoresindicating more impairment of quality of life.

‡‡ The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which measures general health status, includes physical andmental component scores. The scores range from 0 to 100, with higher scores indicating better well-being.




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disease severity at baseline, including PASI scoreand percentage of body-surface area affected, weregenerally similar across the groups.

Most of the patients had received prior topicaltreatments (96% of the patients in the combinedbrodalumab groups and 90% in the placebo group)and prior systemic therapy (78% in the combinedbrodalumab groups and 71% in the placebo group)(Table 1 ). The majority of patients (55%) had re-ceived prior phototherapy, and 35% of the patientshad received prior biologic therapy. Overall, 92% ofthe patients in the brodalumab groups and 84% inthe placebo group received all the planned dosesof the study drug. A total of eight patients usedconcomitant topical glucocorticoids before the

week 12 assessment of the primary end point:seven patients (one in the placebo group, one inthe 70-mg brodalumab group, one in the 140-mgbrodalumab group, two in the 210-mg brodal u-mab group, and two in the 280-mg brodalumabgroup) used various formulations of hydrocorti-sone cream, and one patient in the 210-mg bro-dalumab group used a disallowed product (beta-methasone dipropionate, which is a class IIglucocorticoid).

Efficacy

At week 12, the mean percentage improvement inthe PASI score was significantly greater in all thebrodalumab groups than in the placebo group(P


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epidermal thickness decreased significantly in the280-mg group.

At the week-16 assessment (6 weeks after thelast dose of study drug in the 70-mg, 140-mg, and210-mg brodalumab groups and 8 weeks after thelast dose in the 280-mg group), the mean percent-age 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, respec-tively, as compared with 13.5% in the placebogroup (P


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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 immunopatho-genesis of psoriasis has led to the development of

multiple biologic drugs targeting specific mole-cules that are essential for the development of pso-riatic plaques. 27 Overproduction of interleukins17A, 17F, and 17A/F induces the expression ofproinflammatory cytokines with pathologic con-sequences, including the proliferation of kerati-nocytes and inflammation of epithelial cells inpsoriasis. Therapies targeting this pathway, in-cluding interleukin-17 and interleukin-17R, arecurrently under investigation for the treatment of

inflammatory conditions, such as psoriasis andrheumatoid arthritis. 19,28-30 Brodalumab, whichtargets interleukin-17RA, blocks signaling of in-terleukins 17A and 17F and the interleukin-17A/Fheterodimer, all of which play a role in the in-flammation of psoriasis.

Findings from this study support interleukin-17RA as a viable target for the treatment of pso-riasis. Patients in the 140-mg and 210-mg brodal-

umab groups had a mean improvement in thePASI score of about 85% at week 12. Brodalumab,as compared with placebo, was associated with abenefit with respect to the outcomes of 50%, 75%,90%, and 100% improvement in the PASI score;extent of body-surface area affected; score on thestatic physician’s global assessment; score onthe DLQI; and skin biomarker measurements. In11 of 12 biopsy specimens from patients in thethree higher-dose brodalumab groups, the histo-

Table 2. Clinical Responses at Week 12.*

ResponsePlacebo(N = 38) Brodalumab

70 mg(N = 39)

140 mg(N = 39)

210 mg(N = 40)

280 mg(N = 42)

Improvement in PASI score — no. of patients (%)

50% 6 (16) 20 (51)† 35 (90)† 36 (90)† 34 (81)†75% 0 13 (33)† 30 (77)† 33 (82)† 28 (67)†90% 0 7 (18)‡ 28 (72)† 30 (75)† 24 (57)†

100% 0 4 (10)§ 15 (38)† 25 (62)† 12 (29)†Static physicians’ global assessment of clear or minimal disease — no. (%) 1 (3) 10 (26)‡ 33 (85)† 32 (80)† 29 (69)†Body-surface area affected

Mean percentage 22.5±13.4 14.8±17.2‡ 3.8±5.5† 3.0±5.6† 5.2±7.4†Mean improvement from baseline — percentage points 0.9±9.7 9.2±11.2‡ 21.1±16.9† 22.1±15.0† 16.1±11.4†

DLQI score 10.3±7.6 6.5±6.9‡ 2.0±3.1† 2.0±3.9† 3.9±5.1†SF-36 score

Physical component 50.1±10.5 51.9±8.4 54.8±6.1‡ 52.1±7.8 52.5±8.2Mental component 46.9±11.2 47.8±12.0 51.9±9.1§ 53.8±7.5‡ 50.9±9.1

Skin biomarkers¶Change from baseline in epidermal thickness — µm 24±126 –93±246 –168±92§ –223±25§ –162±77§Negative staining for keratin-16 — no. of specimens/total no.∥ 1/4 2/4 4/5 3/3 3/3Change from baseline in dermal CD3 — cells/mm 48±190 –304±229§ –201±136§ –195±88§ –182±84

* Plus–minus values are means ±SD.† P


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logic and diagnostic features of psoriasis, in-cluding T-cell inf iltration and suprabasal expres-sion of K16, were no longer seen. This findingindicates a reversal of regenerative epidermal mat-uration, which is the essential pathological char-acteristic of psoriasis that causes epidermal hyper-plasia and abnormal differentiation, with scalingand thickness as the clinical correlates. Althoughpatients in all the brodalumab groups had sig-nificant improvement in efficacy measures ascompared with patients in the placebo group,the efficacy results were generally better for pa-tients in the higher-dose groups than for thosein the 70-mg group, suggesting that there is a

dose–response effect.Overall, adverse events occurred with greaterfrequency in the brodalumab groups than in theplacebo group. Two cases of grade 3 asymptom-atic neutropenia (one of which was a serious ad-

verse event) were reported in the 210-mg brodal-umab group. Neutropenia and leukopenia havebeen observed during treatment with other anti–interleukin-17 biologic therapies (monoclonal an-tibodies to interleukin-17A) in patients with rheu-

matoid arthritis. 28 The exact mechanism forneutropenia is not known; however, in animalmodels, interleukin-17 is involved in neutrophilhomeostasis through granulocyte colony-stimu-lating factor, and interleukin-17R–deficient micehave lower levels of neutrophils than do wild-typemice. 31,32 This trial was not large enough or oflong enough duration to assess the risk of infec-tion or cardiovascular events in the brodalumabgroups as compared with the placebo group.

In summary, in this phase 2 study, brodalumabshowed a high level of efficacy in patients withmoderate-to-severe plaque psoriasis, with a rapidonset of action. These findings also support the

important role of interleukin-17RA in the patho-genesis of psoriasis.Supported by Amgen.Dr. Papp reports receiving consulting fees from Abbott, Am-

gen, Astellas, Celgene, Centocor, Eli Lilly, Galderma, GracewayPharmaceuticals, Janssen, Johnson & Johnson, Merck, Norvar-tis, 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, Glaxo-SmithKline, Graceway Pharmaceuticals, Janssen, Johnson &

Johnson, Medimmune, Merck, Novartis, Pfizer, Stiefel, and

Table 3. Adverse Events.

VariablePlacebo(N = 37) Brodalumab

70 mg(N = 38)

140 mg(N = 39)

210 mg(N = 40)

280 mg(N = 41)

Total(N = 158)

number of patients (percent)

Adverse eventsAny 23 (62) 26 (68) 27 (69) 33 (82) 30 (73) 116 (73)Serious* 1 (3) 1 (3) 0 1 (2) 0 2 (1)Leading to withdrawal from study 0 0 0 0 1 (2) 1 (1)Leading to discontinuation of study drug 1 (3) 0 0 2 (5) 1 (2) 3 (2)Grade 3, 4, or 5† 2 (5) 1 (3) 1 (3) 3 (8) 2 (5) 7 (4)

Common adverse events‡Nasopharyngitis 3 (8) 6 (16) 1 (3) 4 (10) 2 (5) 13 (8)Upper respiratory tract infection 2 (5) 3 (8) 3 (8) 2 (5) 5 (12) 13 (8)Arthralgia 1 (3) 1 (3) 2 (5) 0 4 (10) 7 (4)Injection-site erythema 1 (3) 1 (3) 1 (3) 3 (8) 4 (10) 9 (6)

Pain in extremity 0 1 (3) 0 3 (8) 4 (10) 8 (5)Nausea 1 (3) 4 (11) 1 (3) 1 (2) 0 6 (4)

* A serious adverse event was defined as an event that was fatal or life threatening, required or prolonged hospitaliza-tion, or caused persistent or substantial disability or incapacity or a congenital anomaly or birth defect or an event thatwas considered by the investigator to be a medically important event.

† The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria forAdverse Events, version 4.0.

‡ Common adverse events were those that were reported in at least four patients in any treatment group.




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UCB; Dr. Leonardi, receiving consulting fees from Abbott, Am-gen, Centocor, Eli Lilly, and Pfizer, lecture fees from Abbott andAmgen, and investigator fees from Abbott, Amgen, Celgene,Centocor, Galderma, GlaxoSmithKline, Incyte, Maruho, Novar-tis, Novo Nordisk, Pfizer, Schering-Plough (now Merck), Sirt ris,Stiefel, Vascular Biogenics, and Wyeth (now Pfizer); Dr. Menter,receiving consulting fees from Abbott, Amgen, Astellas, Cento-cor, Galderma, Genentech, and Wyeth, lecture fees from Abbott ,Amgen, Centocor, Galderma, and Wyeth, and fees for expert

testimony from Galderma; Dr. Krueger, receiving consultingfees from Centocor, Eli Lilly, and Pfizer and grant support from

Amgen, Centocor, Eli Lilly, Merck, and Pfizer; and Drs. Kriko-rian, Aras, Li, Russell, Thompson, and Baumgartner being full-time employees of Amgen. No other potential conflict of inter-est was relevant to this article was reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Rick Davis, M.S., R.Ph., of Complete Healthcare Com-munications (whose work was funded by Amgen) and EdwardMancini, D.P.M., and Meera Kodukulla, Ph.D., of Amgen for as-

sistance with the writing of the manuscript; and Ryan Athearnof Amgen for assistance with clinical-trial management.

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