ARTHRITIS & RHEUMATISM

Vol. 62, No. 4, April 2010, pp 929–939

DOI 10.1002/art.27334
© 2010, American College of Rheumatology

LY2439821, a Humanized Anti–Interleukin-17 Monoclonal

Antibody, in the Treatment of Patients With
Rheumatoid Arthritis

A Phase I Randomized, Double-Blind, Placebo-Controlled,

Proof-of-Concept Study

M. C. Genovese,1 F. Van den Bosch,2 S. A. Roberson,3 S. Bojin,4 I. M. Biagini,5 Peter Ryan,6

and J. Sloan-Lancaster3

Objective. We undertook this study to evaluate with a total evaluation period of 16 weeks. End points
safety, tolerability, pharmacokinetics, pharmacodynam- included safety, tolerability, pharmacokinetics/
ics, and efficacy of LY2439821, a humanized anti– pharmacodynamics, and efficacy (Disease Activity Score
interleukin-17 (anti–IL-17) monoclonal antibody, in a in 28 joints [DAS28] and percentages of patients meet-
first in-human trial in rheumatoid arthritis (RA) pa- ing American College of Rheumatology 20%, 50%, or
tients taking oral disease-modifying antirheumatic 70% improvement criteria [achieving an ACR20,
drugs (DMARDs). ACR50, or ACR70 response]). The primary efficacy end
Methods. This randomized, double-blind, placebo- point was the DAS28 at week 10.
controlled study consisted of 2 parts. In part A, 20 Results. Baseline characteristics were similar
patients received 1 intravenous (IV) dose of LY2439821 across all groups. Changes in the DAS28 were signifi-
(0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo cantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-
followed by 8 weeks of evaluation. End points included LY2439821–combined groups (ⴚ2.3, ⴚ2.4, and ⴚ2.3,
safety, tolerability, and pharmacokinetics. In part B, 77 respectively) than in the placebo group (ⴚ1.7) at week
patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 10 (P < 0.05), and these differences were significant as
mg/kg) or placebo every 2 weeks for a total of 5 doses, early as week 1. Percentages of ACR20, ACR50, and
ACR70 responses as well as improvements in the ACR
Supported by Chorus, a Division of Eli Lilly. core set of measures were greater in LY2439821-treated
1
M. C. Genovese, MD: Stanford University, Palo Alto, Cali- patients than in placebo-treated patients at multiple
2
fornia; F. Van den Bosch, MD, PhD: University Hospital Ghent,
Ghent, Belgium; 3S. A. Roberson, BSPH, J. Sloan-Lancaster, PhD: time points. There was no apparent dose-response rela-
Chorus, Eli Lilly, Indianapolis, Indiana; 4S. Bojin, PhD: County tionship in treatment-emergent adverse events.
Emergency Hospital of St. Gheorghe, Covasna, Romania; 5I. M. Conclusion. LY2439821 added to oral DMARDs
Biagini, MD: Bacau County Emergency Hospital, Bacau, Romania;
6
Peter Ryan, MB, BS, FRACP: Nucleus Network, Melbourne, Victo- improved signs and symptoms of RA, with no strong
ria, Australia. adverse safety signal noted. This first evaluation of
Dr. Genovese has received consulting fees from Eli Lilly, LY2439821 supports neutralization of IL-17 as a poten-
Novartis, Schering-Plough, and Amgen (less than $10,000 each). Ms
Roberson owns stock or stock options in Eli Lilly. Dr. Ryan has tial novel goal for the treatment of RA.
received speaking fees from Eli Lilly (less than $10,000 each). Dr.
Sloan-Lancaster owns stock or stock options in Eli Lilly and has The treatment of rheumatoid arthritis (RA) has
received patents and has patent applications pending for compounds
that are not related to this study. traditionally included corticosteroids and conventional
Address correspondence and reprint requests to M. C. disease-modifying antirheumatic drugs (DMARDs).
Genovese, MD, Stanford University, 1000 Welch Road, Suite 203, While these therapies provide some benefit, their effi-
Palo Alto, CA 94304. E-mail: [email protected].
Submitted for publication October 9, 2009; accepted in re- cacy has been limited. Newer, biologically-based thera-
vised form December 28, 2009. pies include molecules that inhibit cytokine activity
929
930 GENOVESE ET AL

(tumor necrosis factor [TNF] inhibitors, interleukin-1 on the above-described data, blocking IL-17 is predicted
receptor antagonist [IL-1Ra], or anti–IL-6R monoclonal to be beneficial in the treatment of RA and other
antibody), block T cell–mediated costimulation (CTLA- autoimmune diseases.
4Ig), or modify B cell biology (anti-CD20) (1–3). These This study is the first evaluation of the tolerabil-
therapies have been effective in moderate-to-severe RA ity, pharmacokinetics, and pharmacodynamics of
and have slowed disease progression, as determined LY2439821 in humans, and was a combined single/
radiographically, particularly when combined with meth- multiple dose administration, randomized, double-blind,
otrexate (MTX). However, less than two-thirds of the placebo-controlled, phase I study in RA patients taking
patients treated in pivotal trials meet at least the Amer- background oral DMARDs. Tolerability and pharmaco-
ican College of Rheumatology 50% improvement crite- kinetics were evaluated after a single escalating dose in
ria (achieve at least an ACR50 response) (4), and part A, and tolerability, pharmacokinetics, pharmaco-
disease remission (a Disease Activity Score in 28 joints dynamics, and efficacy were evaluated after multiple
[DAS28] ⬍2.6 [5]) is achieved by only a small minority dosing in part B.
of these patients (3,6–9).
IL-17 (or IL-17A) is a proinflammatory cytokine
PATIENTS AND METHODS
produced primarily by a subset of CD4⫹ T cells, called
Th17 cells, which represent a third subset of CD4⫹ Patients. Patients enrolled were ages 18–75 years and
“helper” lymphocytes in addition to the classically de- were diagnosed as having RA according to the 1987 revised
criteria of the ACR (formerly, the American Rheumatism
scribed Th1 and Th2 populations (10,11). Th17 cells Association) (22) with a global functional class of I, II, or III
likely evolved to provide adequate immunity to specific according to the ACR 1991 revised criteria (23). Inclusion
classes of pathogens, such as extracellular bacteria and criteria included weight of 40–86 kg (inclusive) and the stable
fungi, through the role of IL-17 in the generation and use of ⱖ1 DMARDs for a minimum of 4 weeks prior to the
recruitment of neutrophils (12–14). However, aberrant study (MTX 7.5–25 mg/week, hydroxychloroquine [HCQ]
ⱕ400 mg/day, sulfasalazine [SSZ] 1,000–3,000 mg/day, lef-
Th17 responses and IL-17 production have been impli- lunomide 5–20 mg/day, or azathioprine ⱕ150 mg/day or
cated in a variety of autoimmune diseases, including RA 2 mg/kg/day). Combinations of MTX, HCQ, and/or SSZ were
(15,16). allowed. Females of childbearing potential used appropriate
IL-17 could contribute to the pathogenesis of RA contraception, as defined in the protocol. Additionally, pa-
in several ways, some in synergy with TNF␣ and/or IL-1␤ tients entering part B of the study must have experienced an
insufficient response to at least 1, but not more than 5, oral
and others independently of these 2 cytokines. Under DMARDs and must have had ⱖ6 tender joints and ⱖ6 swollen
normal conditions, levels of IL-17 are extremely low or joints (28-joint assessment) as well as either C-reactive protein
undetectable in human sera; however, 2 studies have ⬎1.5 mg/dl or erythrocyte sedimentation rate ⱖ28 mm/hour at
shown elevated levels in sera and synovial fluid in a the time of screening for the study.
subset of patients with RA (17,18). Additionally, Primary exclusion criteria included the use of ritux-
imab within 6 months, abatacept within 3 months, infliximab,
Chabaud et al demonstrated that RA synovial tissue adalimumab, cyclosporine, or mycophenolic acid within 2
explants produce biologically active IL-17 in addition to months, and etanercept or anakinra within 28 days prior to
IL-6, TNF, and IL-1␤ (19). Immunohistochemical stain- study randomization. Evidence of any active or recent infec-
ing of RA synovium has identified a subset of infiltrating tions, or a history of malignancy or other autoimmune disease,
T cells expressing IL-17 (19,20). were also exclusion criteria. Patients in part B were also
excluded if the use of etanercept, adalimumab, infliximab,
In preclinical studies, IL-17 has been shown to anakinra, or abatacept was discontinued for lack of efficacy.
contribute to joint inflammation and destruction, as well Patients could participate in only one part of the study.
as to bone erosion, and these activities are, in part, Study design. This was a randomized, double-blind,
independent of IL-1␤. Additionally, blockade of IL-17 placebo-controlled study of LY2439821 conducted at 17 sites
by antibody or soluble receptors reduces inflammation in Australia, Belgium, and Romania between November 2006
and February 2008. LY2439821 and placebo were adminis-
and bone erosion in various animal arthritis models (21). tered by intravenous infusion (1 hour). Randomization during
Thus, blocking the biologic activity of IL-17 is predicted part A was performed manually by a study drug coordinator,
to be beneficial in the treatment of RA, potentially re- and part B used an interactive voice response system for
ducing joint inflammation and preventing bone erosion. randomization. All study personnel remained blinded to treat-
LY2439821 is a humanized monoclonal antibody ment until study completion. The dose levels of LY2439821
administered in the study were determined based on the results
(IgG4) that binds to and neutralizes the biologic effects of previous preclinical studies (unpublished data).
of IL-17. It is highly specific to IL-17, with no binding to In part A, patients were given a single escalating
other IL-17 family members (unpublished data). Based intravenous (IV) dose of LY2439821 or placebo (5 patients per
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 931

Table 1. Demographic and baseline characteristics of the patients for part A; single dose escalation*
LY2439821

Placebo 0.06 mg/kg 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg

(n ⫽ 4) (n ⫽ 4) (n ⫽ 4) (n ⫽ 4) (n ⫽ 4) P†
Age, years 41.3 ⫾ 13.8 65.3 ⫾ 7.8 51.7 ⫾ 13.0 51.1 ⫾ 14.2 49.3 ⫾ 9.7 0.069‡
Weight, kg 75.5 ⫾ 11.0 72.3 ⫾ 12.8 70.3 ⫾ 12.3 74.3 ⫾ 11.8 64.5 ⫾ 5.5 0.606‡
BMI, kg/m2 27.8 ⫾ 3.4 27.2 ⫾ 5.2 25.6 ⫾ 6.0 27.6 ⫾ 4.4 23.9 ⫾ 2.5 0.619‡
No. of men/women 1/3 2/2 2/2 2/2 0/4 0.637§
ACR functional class, no. (%) 0.346¶
I 2 (50.0) 3 (75.0) 2 (50.0) 2 (50.0) 2 (50.0) –
II 0 (0.0) 1 (25.0) 2 (50.0) 2 (50.0) 0 (0.0) –
III 2 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (50.0) –
Disease duration, years 7.7 ⫾ 5.66 22.0 ⫾ 8.02 5.6 ⫾ 3.76 8.0 ⫾ 5.68 6.0 ⫾ 4.60 0.004¶
Glucocorticoid use
Yes, no. (%) 1 (25.0) 4 (100.0) 1 (25.0) 3 (75.0) 1 (25.0) –
Daily dose, mg 50.0# 6.3 ⫾ 2.99 5.0# 10.0 ⫾ 5.00 0.5# ⬍0.001¶
MTX use
Yes, no. (%) 4 (100.0) 4 (100.0) 3 (75.0) 2 (50.0) 4 (100.0) –
Weekly dose, mg 19.4 ⫾ 5.15 12.5 ⫾ 2.89 11.7 ⫾ 2.89 20.0 ⫾ 0.00 19.4 ⫾ 14.77 0.684¶
HCQ use
Yes, no. (%) 2 (50.0) 0 (0.0) 2 (50.0) 0 (0.0) 0 (0.0) –
Daily dose, mg 300.0 ⫾ 141.4 – 200.00 ⫾ 0.00 – – ⬍0.001
Leflunomide use
Yes, no. (%) 0 (0.0) 1 (25.0) 0 (0.0) 2 (50.0) 0 (0.0) –
Daily dose, mg – 20.0# – 20.0 ⫾ 0.00 – –
Concomitant DMARD use,
no. (%)
One DMARD 1 (25.0) 3 (75.0) 3 (75.0) 4 (100.0) 4 (100.0) –
Two DMARDs 2 (50.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) –
Three DMARDs 1 (25.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) –

* Except where indicated otherwise, values are the mean ⫾ SD. BMI ⫽ body mass index; ACR ⫽ American College of Rheumatology; MTX ⫽
methotrexate; HCQ ⫽ hydroxychloroquine; DMARD ⫽ disease-modifying antirheumatic drug.
† P values are for overall comparison, and nonsignificance indicates randomization was done appropriately for demographic categories (age, sex,
etc.).
‡ By analysis of variance with treatment and center as fixed factors.
§ By Fisher’s exact test.
¶ By analysis of covariance with treatment and center as fixed effects for continuous variables and by Fisher’s exact test for categorical variables.
# Unable to estimate SD or SD not calculated.

dose level; 1 randomized to placebo and 4 randomized to ACR core set of measures (24) (swollen joint count, tender
LY2439821 at 0.06, 0.2, 0.6, or 2.0 mg/kg). Escalation to the joint count, patient’s assessment of pain, patient’s and physi-
next LY2439821 dose level required acceptable safety data cian’s global assessments of disease activity, Health Assess-
from all patients in the previous cohort through 24 hours ment Questionnaire disability index [HAQ DI] score [25], and
postdosing and from at least 2 LY2439821-treated patients levels of acute-phase reactants) at various time points. Phar-
through 1 week postdosing. In order to maintain the blind, macokinetic parameters were also assessed.
safety data through 1 week postdosing for the first 3 dosed Regulatory and Ethical Review Board approvals from
patients were required prior to each safety review. Safety data competent authorities in each country were obtained for the
from all patients in part A through a minimum of 3 weeks study protocol. All patients signed an informed consent docu-
postdosing were reviewed by a formally constituted internal ment, and the study was conducted in accordance with the
safety assessment committee prior to the commencement of Declaration of Helsinki and following Good Clinical Practice
part B. Primary end points included safety and tolerability. guidelines.
Pharmacokinetic parameters after a single dose were also Statistical analysis. Baseline values were compared
evaluated. using an analysis of variance model. Covariates taken into
Patients (total of 77) in part B were assigned by consideration included treatment and center. For numeric
parallel randomization to treatment with placebo or with 0.2, continuous efficacy measures in part B, an analysis of covari-
0.6, or 2.0 mg/kg LY2439821 administered IV every 2 weeks ance (ANCOVA) model was used that included treatment and
for a total of 5 treatments. Patients were then followed up for center as fixed effects and the baseline measurement as a
an additional 8 weeks after the final infusion. Primary end covariate. Pairwise comparisons between each dose and pla-
points included safety and the DAS28 at week 10. Secondary cebo were made using the ANCOVA model. For categorical
end points included percentages of patients achieving ACR20, efficacy response measures, a 2-sided Cochran-Mantel-
ACR50, and ACR70 responses as well as improvements in the Haenszel test was used, adjusted for center between each
932 GENOVESE ET AL

Table 2. Demographic and baseline characteristics of the patients for part B; multiple dose*
LY2439821

Placebo 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg

(n ⫽ 18) (n ⫽ 19) (n ⫽ 20) (n ⫽ 20) P†
Age, years 54.4 ⫾ 9.7 59.6 ⫾ 8.4 57.7 ⫾ 11.5 55.6 ⫾ 8.2 0.464‡
Weight, kg 68.1 ⫾ 12.7 67.3 ⫾ 13.2 67.6 ⫾ 11.5 65.3 ⫾ 11.6 0.882‡
BMI, kg/m2 26.6 ⫾ 4.5 25.4 ⫾ 4.3 27.2 ⫾ 3.9 24.7 ⫾ 4.2 0.272‡
Sex, no. (%) 0.080§
Male 0 (0) 3 (15.8) 1 (5.0) 5 (25.0) –
Female 18 (100) 16 (84.2) 19 (95.0) 15 (75.0) –
ACR functional class, no. (%) 0.211¶
I 3 (16.7) 3 (15.8) 5 (25.0) 1 (5.0) –
II 5 (27.8) 8 (42.1) 5 (25.0) 13 (65.0) –
III 10 (55.6) 8 (42.1) 10 (50.0) 6 (30.0) –
Disease duration, years 6.5 ⫾ 5.67 10.5 ⫾ 13.02 10.9 ⫾ 10.21 6.1 ⫾ 5.48 0.268¶
Swollen joint count, 0–28 12.9 ⫾ 4.18 12.4 ⫾ 5.35 13.7 ⫾ 5.38 11.8 ⫾ 4.95 0.314¶
Tender joint count, 0–28 18.2 ⫾ 4.71 17.3 ⫾ 6.30 16.8 ⫾ 6.34 15.7 ⫾ 7.55 0.458¶
DAS28 6.1 ⫾ 0.74 6.0 ⫾ 0.68 6.0 ⫾ 0.83 5.8 ⫾ 0.86 0.517¶
CRP, mg/dl 2.47 ⫾ 3.21 1.90 ⫾ 2.16 1.80 ⫾ 1.81 2.15 ⫾ 3.01 0.891¶
ESR, mm/hour 64.3 ⫾ 25.24 61.0 ⫾ 26.03 63.6 ⫾ 23.99 69.1 ⫾ 26.26 0.783¶
RF titer, IU/ml 125.2 ⫾ 243.95 69.1 ⫾ 82.13 275.6 ⫾ 597.49 130.1 ⫾ 181.54 0.266¶
HAQ DI score 1.8 ⫾ 0.48 1.7 ⫾ 0.55 1.8 ⫾ 0.66 1.4 ⫾ 0.74 0.065¶
Glucocorticoid use
Yes, no. (%) 6 (33.3) 4 (21.1) 6 (30.0) 8 (40.0) –
Daily dose, mg 5.7 ⫾ 2.66 4.9 ⫾ 1.75 3.7 ⫾ 0.82 5.1 ⫾ 2.59 0.485¶
MTX use
Yes, no. (%) 7 (38.9) 9 (47.4) 8 (40.0) 7 (35.0) –
Weekly dose, mg 12.9 ⫾ 3.93 10.5 ⫾ 2.67 9.7 ⫾ 3.12 12.1 ⫾ 2.67 0.006¶
HCQ use
Yes, no. (%) 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) –
Daily dose, mg – – 200.0# – –
Leflunomide use
Yes, no. (%) 10 (55.6) 6 (31.6) 8 (40.0) 10 (50.0) –
Daily dose, mg 20.0 ⫾ 0.00 20.0 ⫾ 0.00 20.0 ⫾ 0.00 19.0 ⫾ 3.16 0.510
Concomitant DMARD use, no. (%)
One DMARD 1 (5.6) 1 (5.3) 2 (10.0) 1 (5.0) –
Two DMARDs 15 (83.3) 16 (84.2) 14 (70.0) 17 (85.0) –
Three DMARDs 2 (11.1) 2 (10.5) 4 (20.0) 2 (10.0) –

* Except where indicated otherwise, values are the mean ⫾ SD. DAS28 ⫽ Disease Activity Score in 28 joints; CRP ⫽ C-reactive protein; ESR ⫽
erythrocyte sedimentation rate; RF ⫽ rheumatoid factor; HAQ DI ⫽ Health Assessment Questionnaire disability index (see Table 1 for other
definitions).
† P values are for overall comparison, and nonsignificance indicates randomization was done appropriately for demographic categories (age, sex,
etc.).
‡ By analysis of covariance (ANCOVA) with treatment and center as fixed factors.
§ By 2-sided Cochran-Mantel-Haenszel test adjusted for center (general association).
¶ By ANCOVA with treatment and center as fixed effects for continuous variables and by Cochran-Mantel-Haenszel test for categorical variables.
# Unable to estimate SD or SD not calculated.

LY2439821 group and the placebo group. If any analytic group assumed a common SD of 1.35 and did not include any
had fewer than 5 subjects, the 1-sided Fisher’s exact test was adjustments for multiplicity. Such power assumptions were
used in place of the Cochran-Mantel-Haenszel test. No adjust- deemed appropriate for a first in-human proof-of-concept
ments for multiplicity were made. Pharmacokinetic parameters study. For a 2-sided analysis, with all other assumptions as
were derived using a 2-compartment pharmacokinetic model above, 21 patients per group would have been required.
employing WinNonlin Professional, version 5.2 (Pharsight,
Mountain View, CA). Safety assessments were summarized
RESULTS
descriptively by treatment group.
In part A, 20 patients were considered sufficient to Patient baseline demographics, characteristics,
determine safety and pharmacokinetics. In part B, completion
by 17 patients in each treatment group provided 80% power to and disposition. Patients in part A were generally simi-
detect a treatment difference in the DAS28 of 1.2 at a lar across treatment groups (Table 1). The only signifi-
significance level of 0.05, using a 1-sided 2-sample t-test. This cant differences in treatment groups occurred in disease
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 933

Table 3. Treatment-emergent adverse events by preferred term occurring in ⱖ2 patients from all LY2439821-treated groups combined (part A)
or in ⬎3% of patients from all LY2439821-treated groups combined (part B)*
LY2439821

All
LY2439821-treated
Preferred term Placebo 0.06 mg/kg 0.2 mg/kg 0.6 mg/kg 2.0 mg/kg groups
Part A
Diarrhea 0 (0.0) 1 (25.0) 1 (25.0) 1 (25.0) 1 (25.0) 4 (25.0)
Abdominal pain 0 (0.0) 0 (0.0) 2 (50.0) 0 (0.0) 0 (0.0) 2 (12.5)
Vomiting 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0) 1 (25.0) 2 (12.5)
Fatigue 0 (0.0) 0 (0.0) 0 (0.0) 2 (50.0) 0 (0.0) 2 (12.5)
Back pain 0 (0.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) 2 (12.5)
Headache 4 (100.0) 1 (25.0) 2 (50.0) 2 (50.0) 3 (75.0) 8 (50.0)
Paresthesia 0 (0.0) 1 (25.0) 1 (25.0) 0 (0.0) 0 (0.0) 2 (12.5)
Part B
Leukopenia 0 (0.0) – 1 (5.3) 1 (5.0) 2 (10.0) 4 (6.8)
Neutropenia 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)
Vertigo 0 (0.0) – 1 (5.3) 1 (5.0) 2 (10.0) 4 (6.8)
Pharyngitis 0 (0.0) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Rhinitis 1 (5.6) – 0 (0.0) 3 (15.0) 0 (0.0) 3 (5.1)
Urinary tract infection 1 (5.6) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Influenza 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)
Headache 1 (5.6) – 1 (5.3) 1 (5.0) 1 (5.0) 3 (5.1)
Hypotension 0 (0.0) – 1 (5.3) 1 (5.0) 0 (0.0) 2 (3.4)

* Values are the number (%) of patients experiencing an event. All adverse events listed were coded using the Medical Dictionary for Regulatory
Activities, version 10.0. In part A, there were 4 patients in the placebo-treated group and 4 patients in each of the LY2439821-treated groups, for
a total of 16 patients in all of the LY2439821-treated groups combined. In part B, there were 18 patients in the placebo-treated group, 19 patients
in the 0.2 mg/kg LY2439821-treated group, and 20 patients in each of the 0.6 mg/kg and 2.0 mg/kg LY2439821-treated groups, for a total of 59
patients in all of the LY2439821-treated groups combined.

duration and in HCQ and glucocorticoid use. For dis- from 3 study centers in Belgium and 72 subjects from 11
ease duration, the 0.06 mg/kg treatment group had RA study centers in Romania). Study drug treatment was
for an average of 22 years compared with an average of discontinued for 3 patients due to AEs (1 patient in the
5.6–8 years in all other groups. For HCQ use, the 0.6 mg/kg group experienced worsening of arthritis; 2
placebo and the 0.2 mg/kg treatment groups had mean patients in the 2.0 mg/kg group experienced moderate
daily doses of 300 mg and 200 mg, respectively (2 of 4 leukopenia [white blood cell count ⬎2,200/␮l but
patients per group taking HCQ), while no patients in the ⬍3,000/␮l]). Treatment for 1 patient in the 2.0 mg/kg
other treatment groups were taking HCQ. For glucocor- group was discontinued due to an abnormal pretreat-
ticoid use, the placebo and the 2.0 mg/kg groups had ment alanine aminotransferase concentration of 158
mean daily doses of 50 mg and 0.5 mg, respectively, units/liter discovered after the first dose of study drug
compared with mean daily doses of 5–10 mg for the had been administered.
other groups. In the placebo group, only 1 patient took Safety. AEs. Table 3 presents treatment-emergent
a concomitant glucocorticoid, at a dose of 25 mg twice a AEs occurring in ⱖ2 of the all-LY2439821–combined
day. Dose for concomitant glucocorticoid use was not patients in part A or in ⬎3% of the all-LY2439821–
restricted as a criterion for entry into part A of the study. combined patients in part B. The term “all-LY2439821–
In part B, there was a statistically significant difference combined patients” refers to the combined results from
in the mean weekly dose of MTX; otherwise, patient all of the LY2439821-treated groups within either part A
demographics and baseline characteristics were similar or part B of the study.
across treatment groups (Table 2). In part A, headache was the most common
Part A enrolled 20 patients across 5 treatment treatment-emergent AE and occurred most frequently
groups at 2 study centers in Australia. No patients in the placebo group (Table 3). The most common
withdrew from part A due to adverse events (AEs); 2 treatment-emergent AEs occurring in patients who re-
patients withdrew for other causes (1 relocated and 1 ceived LY2439821 were headache (8 patients compared
withdrew based on investigator’s decision). Part B en- with all 4 placebo-treated patients, all of mild or mod-
rolled 77 patients across 4 treatment groups (5 subjects erate intensity, and all resolved) and diarrhea (4 patients
934 GENOVESE ET AL

compared with no placebo-treated patients, all of mild ceived 0.6 mg/kg LY2439821, and one received 2.0 mg/
or moderate intensity, and all resolved). There were no kg LY2439821 (the lowest recorded neutrophil count
serious AEs noted in part A. was 1,040/␮l at week 6). None of the patients discontin-
In part B, the most common treatment-emergent ued the study due to neutropenia.
AEs that occurred in all-LY2439821–combined patients Infections. The frequency of infections was low in
were leukopenia and vertigo (4 patients for both, com- this study. Pharyngitis, rhinitis, urinary tract infections,
pared with no placebo-treated patients for either), while and influenza were the only infections reported in ⬎3%
rhinitis was the most common treatment-emergent AE of the all-LY2439821–combined patients in part B.
occurring in any individual LY2439821 treatment group Rhinitis and urinary tract infections also occurred in the
(3 patients, all in the 0.6 mg/kg group, compared with 1 placebo group; however, pharyngitis and influenza did
placebo-treated patient) (Table 3). There was no appar- not. The most frequently occurring infection in any one
ent dose-response relationship in treatment-emergent treatment group was rhinitis, which occurred in 3 pa-
AEs. One serious AE occurred in the 0.6 mg/kg treat- tients taking 0.6 mg/kg LY2439821 (Table 3). Of the
ment group. Three days after the last study drug infu- patients with low white blood cell or neutrophil counts,
sion, the patient reported a skin ulcer that had been only 1 (with both mild leukopenia and mild neutropenia
present for the previous 10 days. The patient was as defined by MedDRA coding) had an infection (of the
hospitalized due to the skin ulcer 13 days after the last urinary tract), which presented and resolved prior to the
dose of study drug. The ulcer improved with treatment, onset of low white blood cell and neutrophil counts, as
and the investigator did not consider the event related to well as a mild bacteriuria, determined by the investigator
study drug or protocol procedures. to be possibly related to the study drug, which presented
after the onset of low white blood cell and neutrophil
Laboratory parameters. Evaluation of laboratory
counts.
parameters indicated that mean changes from baseline
Immunogenicity and allergic and infusion reac-
were generally small and similar across treatment
tions. Anti-LY2439821 antibodies were detected in 2
groups, except for white blood cell, neutrophil, and
patients in part B of the study and at both postdosing
platelet counts, which were slightly but significantly
time points analyzed (week 8 and week 16). Antibodies
decreased in LY2439821-treated groups compared with
were detected in 1 patient each in the 0.2 mg/kg (titer of
the placebo group at several times during the study.
1:2) and 0.6 mg/kg (titer of 1:10) treatment groups.
Mild-to-moderate leukopenia and mild neutropenia
Neither of these patients experienced treatment-
were reported as treatment-emergent AEs in 4 and 2 emergent AEs, and no alterations in pharmacokinetics
patients receiving LY2439821, respectively, compared were noted. No antibodies to LY2439821 were detected
with none in the placebo-treated group (Medical Dictio- in any placebo-treated patients.
nary for Regulatory Activities [MedDRA], version 10.0) One patient in part A (0.2 mg/kg treatment
(Table 3). Based upon Common Terminology Criteria group) experienced an adverse drug reaction, deemed by
for Adverse Events, version 3.0, 3 patients (all treated the investigator to be a case of moderate immune type
with LY2439821) experienced white blood cell counts III reaction. This patient experienced a skin rash and
⬍3,000/␮l during the study, and 5 patients (all treated generalized pruritus, preceded by various symptoms
with LY2439821) experienced neutrophil counts (headache, abdominal pain, diarrhea, somnolence, and
⬍1,500/␮l. There were no cases of thrombocytopenia anorexia) and followed by a delayed increase in trans-
reported during the study. aminases. All clinical symptoms resolved completely,
Of the 3 patients with white blood cell counts and there were no detectable anti-LY2439821 antibodies
⬍3,000/␮l, one received 0.2 mg/kg LY2439821 and two in this patient. Another patient in the 0.2 mg/kg treat-
received 2.0 mg/kg LY2439821 (the lowest recorded ment group in part A experienced infusion site pain.
white blood cell count was 2,290/␮l at week 6). Both There were no other reports of allergic or infusion
patients in the 2.0 mg/kg treatment group were deemed reactions during the study.
to have moderate intensity leukopenia possibly/probably Pharmacokinetics. The pharmacokinetic proper-
related to study treatment, and further study drug ties of LY2439821 were similar in both parts of the
treatment was discontinued for both patients (one after study. The mean terminal elimination half-life ranged
3 doses of LY2439821; one after 4 doses of LY2439821). from 15 to 18 days in part A and from 14 to 16 days in
Of the 5 patients with neutrophil counts part B. Because of the long half-life, accumulation of
⬍1,500/␮l, two received 0.2 mg/kg LY2439821, two re- drug was observed in part B, in which dosing occurred
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 935

Figure 1. Change from baseline in Disease Activity Score in 28 joints (DAS28) by treatment over time, and percentage of patients meeting the
American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response). Values are
the least squares mean per treatment group. A, Change in DAS28 over time. B, ACR20 responses at week 10. The percentages of patients achieving
an ACR20 response were 73.7%, 70.0%, and 90.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821 (LY)–treated groups, respectively,
compared with 55.6% for the placebo-treated group (P ⱕ 0.05 versus placebo for the 2.0 mg/kg group). C, ACR50 responses at week 10. The
percentages of patients achieving an ACR50 response were 42.1%, 40.0%, and 35.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821-treated
groups, respectively, compared with 16.7% for the placebo-treated group. D, ACR70 responses at week 10. The percentages of patients achieving
an ACR70 response were 26.3%, 20.0%, and 25.0% for the 0.2 mg/kg, 0.6 mg/kg, and 2.0 mg/kg LY2439821-treated groups, respectively, compared
with 5.6% for the placebo-treated group. ⴱ ⫽ P ⱕ 0.05 versus placebo.

every 2 weeks. Maximum concentration and area under achieved an ACR20 response at all dose levels by week
the curve in both parts of the study showed dose 2 (26.3%, 30.0%, 45.0%, and 33.9% for 0.2 mg/kg,
proportionality and linear pharmacokinetics across the 0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–combined
doses tested. groups, respectively, compared with 0.0% for the pla-
Efficacy. DAS28 scores. In part B, DAS28 scores cebo group) (Figure 1B). At week 10, the percentages of
decreased as early as week 1 in all LY2439821 dose patients achieving an ACR20 response were 73.7%,
groups relative to placebo, and this observation persisted 70.0%, 90.0%, and 78.0% for the 0.2 mg/kg, 0.6 mg/kg,
to the end of the study (Figure 1A). At week 10, the 2.0 mg/kg, and all-LY2439821–combined groups, respec-
changes from baseline in DAS28 values were ⫺2.3, ⫺2.2, tively (P ⱕ 0.05 versus placebo for the 2.0 mg/kg group),
⫺2.4, and ⫺2.3 in the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg, compared with 55.6% for the placebo group. Also at
and all-LY2439821–combined groups, respectively week 10, percentages of patients achieving ACR50 and
(P ⱕ 0.05 versus placebo for all except the 0.6 mg/kg ACR70 responses in the LY2439821-treated groups (for
group), compared with ⫺1.7 in the placebo group the ACR50 response, 42.1%, 40.0%, 35.0%, and 39.0%
(least squares mean) (Figure 1A). At this time, 73.7%, for the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg, and all-
65.0%, 85.0%, and 74.6% of patients in the 0.2 mg/kg, LY2439821–combined groups, respectively; for the
0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–combined ACR70 response, 26.3%, 20.0%, 25.0%, and 23.7% for
groups, respectively, experienced improvements in the the 0.2 mg/kg, 0.6 mg/kg, 2.0 mg/kg, and all-LY2439821–
DAS28 of ⱖ1.2 compared with 44.4% of placebo-treated combined groups, respectively) were higher than those
patients. in the placebo group (16.7% and 5.6% for ACR50 and
ACR20, ACR50, and ACR70 responses. Signifi- ACR70 responses, respectively) (Figures 1C and D).
cantly greater percentages of patients achieved an Throughout the study, most patients showed improve-
ACR20 response at multiple time points and doses of ments in the ACR core set of measures, with
LY2439821. Significantly greater percentages of patients LY2439821-treated patients showing significant im-
936 GENOVESE ET AL

Figure 2. Responses in American College of Rheumatology core set parameters by treatment over time. A, Swollen joint counts. B, Tender joint
counts. C, Health Assessment Questionnaire disability index (HAQ DI) score. D, Change from baseline in C-reactive protein. Values are the least
squares mean per treatment group. ⴱ ⫽ P ⱕ 0.05 versus placebo. LY ⫽ LY2439821.

provements compared with placebo-treated patients at suggests that IL-17 may have several roles including the
multiple time points (Figures 2 and 3). promotion of neutrophil homeostasis, host defense
against extracellular bacteria and some fungi, and
DISCUSSION chronic pathogenic inflammation such as that found in
autoimmune disease, asthma/allergy, and lung inflam-
IL-17 is a unique proinflammatory cytokine ame- mation (11). There is considerable evidence that IL-17
nable to targeting inflammatory and autoimmune dis- plays an important and nonredundant role in the patho-
eases. This phase I, two-part, single/multiple dose ad- genesis of arthritis in animal models (21).
ministration study in patients with active RA provides
The two-staged design of this trial allowed the
preliminary insight into the safety and potential efficacy
assessment of pharmacokinetics and tolerability with
of targeting this novel pathway. With currently available
single dose administration in RA patients receiving
disease-modifying therapies, less than two-thirds of RA
concomitant DMARD therapy without requiring a par-
patients reach at least an ACR50 response. Further-
more, disease remission (DAS28 ⬍2.6) is achieved by ticular level of active disease to be present. Upon
only a small minority of these patients, emphasizing the satisfactory completion of part A, and with no clear
need to develop novel therapies. The results of this study concerns about tolerability, the study continued with a
demonstrate that neutralization of IL-17 could provide a parallel design in part B, which explored multiple dose
viable goal for future treatment of RA. IL-17 acts as an administration and allowed both safety and efficacy
“effector” cytokine, much like TNF␣. IL-17 can syner- assessments in a population of patients with active RA
gize with other proinflammatory cytokines to stimulate receiving concomitant oral DMARD therapy.
release of additional proinflammatory cytokines and Pharmacokinetic parameters were reproducible
chemokines, nitric oxide, and matrix metalloproteinases across both parts of the study. The half-life was similar
in many cell types. Since the IL-17 receptor is ubiqui- after single and multiple dosing, ranging from 15 to 18
tously expressed, virtually all cell types have been dem- days and from 14 to 16 days, respectively, indicating the
onstrated to have a biologic response to IL-17. Evidence potential for dosing every 2 weeks or less frequently.
ANTI–IL-17 MONOCLONAL ANTIBODY FOR TREATMENT OF RA 937

Tolerability appeared to be favorable, with only 1 seri-

ous AE reported in part B of the study. AEs were also
few, mild to moderate in severity, and did not increase
with drug dose escalation. White blood cell, platelet, and
neutrophil counts were slightly but significantly de-
creased in LY2439821 treatment groups versus the
placebo group at several time points during the study.
Four patients experienced mild-to-moderate leukope-
nia, only 2 patients experienced mild neutropenia ac-
cording to MedDRA, version 10.0 coding (Table 3), and
no patients experienced thrombocytopenia. Given the
low incidence of patients with leukopenia or neutrope-
nia, and the dosing with concomitant medications known
to be associated with decreased blood cell counts, the
causal relationship of these changes to LY2439821 is
unclear. However, IL-17 induces production of granulo-
cyte colony-stimulating factor and other chemokines and
cytokines, contributing to neutrophil progenitor differ-
entiation and maturation (14). Therefore, blocking such
effects with LY2439821 could possibly result in reduced
neutrophil counts.
Because the study was an initial assessment of
LY2439821 in humans, the focus on safety was conser-
vative, and the patients experiencing moderate leukope-
nia were withdrawn due to the potential higher risk of
infection. In a relatively short experimental period,
patients treated with LY2439821 demonstrated robust
and significant improvements in DAS28 scores as well as
significantly greater percentages of ACR20 responses.
Both parameters showed improvements that occurred
early in the study (as early as week 1) and that were
sustained through at least 16 weeks (8 weeks after the
last dose of drug). LY2439821-treated patients also
showed significant improvements at multiple time points
in tender joint count, swollen joint count, patient’s
assessment of pain, patient’s global assessment of dis-
ease activity, and HAQ DI score. The physician’s global
assessment of disease activity decreased in LY2439821-
treated patients but with fewer significant differences
versus placebo than observed for the patient’s global
assessment of disease activity.
Since this was a phase I study, there was a
primary focus on safety and tolerability after both single
and multiple dose administration; thus, efficacy para-
meters were not addressed until part B. Further, despite
the observed efficacy, the study failed to demonstrate a
Figure 3. Responses in American College of Rheumatology core set
clear dose-response relationship between LY2439821
parameters by treatment over time. A, Patient’s assessment of pain.
B, Patient’s global assessment of disease activity. C, Physician’s global and efficacy parameters or with respect to tolerability.
assessment of disease activity. Values are the least squares mean per The 2.0 mg/kg dose, however, did show consistent im-
treatment group. ⴱ ⫽ P ⱕ 0.05 versus placebo. LY ⫽ LY2439821. provements compared with the other dose levels, and
938 GENOVESE ET AL

findings were not meaningfully different with regard to Berclaz, MD, Eiry Roberts, MD, and Olivier Benichou, MD,
safety. A high placebo response (55.6% of placebo- for their contributions in the preparation of the manuscript.
treated patients had an ACR20 response at weeks 10
and 16) was observed in this study. It is not clear whether AUTHOR CONTRIBUTIONS
this observation represents unique features of this study, All authors were involved in drafting the article or revising it
the patient population, the investigators, or access to critically for important intellectual content, and all authors approved
the final version to be published. Dr. Genovese had full access to all of
care in the populations concerned. Despite the placebo the data in the study and takes responsibility for the integrity of the
response, a significant difference was demonstrated be- data and the accuracy of the data analysis.
tween the active treatment and placebo groups in both Study conception and design. Genovese, Roberson, Sloan-Lancaster.
Acquisition of data. Van den Bosch, Roberson, Bojin, Biagini, Ryan.
the DAS28 and the percentages of ACR responders.
Analysis and interpretation of data. Genovese, Sloan-Lancaster.
The DAS28 at week 10 was chosen as the primary
efficacy end point because, as a validated continuous
outcome measure and a frequently used composite index ROLE OF THE STUDY SPONSOR
in RA outside of the US, it allowed for a comparison of As sponsor of the study, Chorus, a Division of Eli Lilly, was
responsible for the creation of the study design, in close collaboration
efficacy with the smaller sample size consistent with with Dr. Genovese. Chorus oversaw the data collection and analysis, as
phase I safety studies. Furthermore, the study was not well as data interpretation. Chorus actively participated in the writing
powered to draw definitive conclusions on dose effects of the manuscript. Eli Lilly approved the content of the submitted
manuscript prior to its submission for publication. Publication of the
or to assess accurately the proportion of ACR respond-
manuscript was contingent on Eli Lilly having an opportunity to review
ers, but rather to provide an early opportunity to assess it prior to its submission.
potential benefit in a multiple dose phase I trial.
Recently, results were presented from a proof-of-
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